Alpha- and beta-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors

ABSTRACT

α- and β-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

RELATED APPLICATION

[0001] This application is a continuation in part application ofco-owned and co-pending PCT/US93/07814, filed Aug. 24, 1993, which is acontinuation in part application of co-owned U.S. patent applicationSerial No. 076/934,984 filed Aug. 25, 1992, now abandoned.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to retroviral protease inhibitorsand, more particularly, relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to sulfonamide-containing hydroxyethylamine proteaseinhibitor compounds, a composition and method for inhibiting retroviralproteases such as human immunodeficiency virus (HIV) protease and fortreating a retroviral infection, e.g., an HIV infection. The subjectinvention also relates to processes for making such compounds as well asto intermediates useful in such processes.

[0004] 2. Related Art

[0005] During the replication cycle of retroviruses, gag and gag-polgene products are translated as proteins. These proteins aresubsequently processed by a virally encoded protease (or proteinase) toyield viral enzymes and structural proteins of the virus core. Mostcommonly, the gag precursor proteins are processed into the coreproteins and the pol precursor proteins are processed into the viralenzymes, e.g., reverse transcriptase and retroviral protease. It hasbeen shown that correct processing of the precursor proteins by theretroviral protease is necessary for assembly of infectious virons. Forexample, it has been shown that frameshift mutations in the proteaseregion of the pol gene of HIV prevents processing of the gag precursorprotein. It has also been shown through site-directed mutagenesis of anaspartic acid residue in the HIV protease that processing of the gagprecursor protein is prevented. Thus, attempts have been made to inhibitviral replication by inhibiting the action of retroviral proteases.

[0006] Retroviral protease inhibition may involve a transition-statemimetic whereby the retroviral protease is exposed to a mimetic compoundwhich binds to the enzyme in competition with the gag and gag-polproteins to thereby inhibit replication of structural proteins and, moreimportantly, the retroviral protease itself. In this manner, retroviralreplication proteases can be effectively inhibited.

[0007] Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. Suchcompounds include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP 0 346 847; EP 0 342,541; Roberts et al,“Rational Design of Peptide-Based Proteinase Inhibitors,” Science, 248,358 (1990); and Erickson et al, “Design Activity, and 2.8A CrystalStructure of a C2 Symmetric Inhibitor Complexed to HIV-1 Protease,”Science, 249, 527 (1990).

[0008] Several classes of compounds are known to be useful as inhibitorsof the proteolytic enzyme renin. See, for example, U.S. Pat. No.4,599,198; U.K. 2,184,730; G.B. 2,209,752; EP 0 264 795; G.B. 2,200,115and U.S. SIR H725. Of these, G.B. 2,200,115, GB 2,209,752, EP 0 264,795,U.S. SIR H725 and U.S. Pat. No. 4,599,198 disclose urea-containinghydroxyethylamine renin inhibitors. EP 468 641 discloses renininhibitors and intermediates for the preparation of the inhibitors,which include sulfonamide-containing hydroxyethylamine compounds, suchas3-(t-butoxycarbonyl)amino-cyclohexyl-1-(phenylsulfonyl)amino-2(5)-butanol.G.B. 2,200,115 also discloses sulfamoyl-containing hydroxyethylaminerenin inhibitors, and EP 0264 795 discloses certainsulfonamide-containing hydroxyethylamine renin inhibitors. However, itis known that, although renin and HIV proteases are both classified asaspartyl proteases, compounds which are effective renin inhibitorsgenerally cannot be predicted to be effective HIV protease inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

[0009] The present invention is directed to virus inhibiting compoundsand compositions. More particularly, the present invention is directedto retroviral protease inhibiting compounds and compositions, to amethod of inhibiting retroviral proteases, to processes for preparingthe compounds and to intermediates useful in such processes. The subjectcompounds are characterized as sulfonamide-containing hydroxyethylamineinhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0010] In accordance with the present invention, there is provided aretroviral protease inhibiting compound of the formula:

[0011] (I)

[0012] or a pharmaceutically acceptable salt, prodrug or ester thereofwherein:

[0013] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, alkynyl, cycloalkyl,aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminocarbonyl andaminoalkanoyl radicals are disubstituted, said substituents along withthe nitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical;

[0014] R′ represents hydrogen, radicals as defined for R³ or R″SO₂—wherein R″ represents radicals as defined for R³; or R and R′ togetherwith the nitrogen to which they are attached represent heterocycloalkyland heteroaryl radicals;

[0015] R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,glycine, allo-threonine, serine, O-alkyl serine, aspartic acid,beta-cyano alanine and valine side chains;

[0016] R¹′ and R¹″ independently represent hydrogen and radicals asdefined for R¹, or one of R¹′ and R¹″, together with R¹ and the carbonatoms to which R¹, R¹′ and R¹″ are attached, represent a cycloalkylradical;

[0017] R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —CN, —CF₃, —OR⁹ and —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals, and halogen radicals;

[0018] R³ represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals, wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical;

[0019] R⁴ represents radicals as defined by R³ except for hydrogen;

[0020] R⁶ represents hydrogen and alkyl radicals;

[0021] x represents 0, 1 or 2;

[0022] t represents either 0 or 1; and

[0023] Y represents O, S and NR¹⁵ wherein R¹⁵ represents hydrogen andradicals as defined for R³.

[0024] A family of compounds of particular interest within Formula I arecompounds embraced by Formula II:

[0025] wherein:

[0026] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or where said aminoalkanoyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical;

[0027] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0028] R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂ (SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,glycine, allo-threonine, serine, O-methyl serine, aspartic acid,beta-cyano alanine and valine side chains;

[0029] R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —C≡N, CF₃, —OR⁹, —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals;

[0030] R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

[0031] R⁴ represents radicals as defined by R³.

[0032] A more preferred family of compounds within Formula II consistsof compounds wherein:

[0033] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or where said aminoalkanoyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical;

[0034] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0035] R¹ represents CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃), C(CH₃)₂(S[O]CH₃),C(CH₃)₂(S[O]₂CH₃), alkyl, alkenyl and alkynyl radicals, and amino acidside chains selected from the group consisting of asparagine, valine,threonine, allo-threonine, isoleucine, tert-leucine, S-methyl cysteineand the sulfone and sulfoxide derivatives thereof, alanine, andallo-isoleucine;

[0036] R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents alkylradicals; and

[0037] R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl and heteroaralkyl radicals.

[0038] Of highest interest are compounds within Formula II wherein

[0039] R represents alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

[0040] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0041] R¹ represents CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃), C(CH₃)₂(S[O]CH₃),C(CH₃)₂(S[O]₂CH₃), methyl, propargyl, t-butyl, isopropyl and sec-butylradicals, and amino acid side chains selected from the group consistingof asparagine, valine, S-methyl cysteine, allo-iso-leucine, iso-leucine,and beta-cyano alanine side chains;

[0042] R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;

[0043] R³ represents isoamyl, n-butyl, isobutyl and cyclohexyl radicals;and

[0044] R⁴ represents phenyl, substituted phenyl and methyl radicals.

[0045] Another family of compounds of particular interest within FormulaI are compounds embraced by Formula III:

[0046] wherein:

[0047] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or where said aminoalkanoyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical;

[0048] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0049] R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃) ₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,glycine, allo-threonine, serine, aspartic acid, beta-cyano alanine andvaline side chains;

[0050] R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radicals, —NO₂, —C≡N, CF₃, —OR⁹, —SR⁹,wherein R⁹ represents hydrogen and alkyl;

[0051] R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

[0052] R⁴ represents radicals as defined by R³.

[0053] A more preferred family of compounds within Formula III consistsof compounds wherein

[0054] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or where said aminoalkanoyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical;

[0055] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0056] R¹ represents hydrogen, alkyl and alkenyl radicals, and aminoacid side chains selected from the group consisting of asparagine,valine, threonine, allo-threonine, isoleucine, tert-leucine, S-methylcysteine and the sulfone and sulfoxide derivatives thereof, alanine, andallo-isoleucine;

[0057] R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl and halogen radicals; and

[0058] R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals.

[0059] Of highest interest are compounds within Formula III wherein

[0060] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminoalkanoyl radical is disubstituted, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical;

[0061] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0062] R¹ represents hydrogen, methyl, propargyl, t-butyl, isopropyl andsec-butyl radicals, and amino acid side chains selected from the groupconsisting of asparagine, valine, S-methyl cysteine, allo-iso-leucine,iso-leucine, threonine, serine, aspartic acid, beta-cyano alanine, andallo-threonine side chains;

[0063] R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals; and

[0064] R³ represents alkyl, cyclohexyl, isobutyl, isoamyl, and n-butylradicals; and

[0065] R⁴ represents methyl, phenyl and substituted phenyl radicalswherein the substituents are selected from halo, alkoxy, hydroxy, nitroand amino substituents.

[0066] Another family of compounds of particular interest within FormulaI are compounds embraced by Formula IV:

[0067] wherein:

[0068] R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl,aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or where said aminoalkanoyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical;

[0069] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

[0070] R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,glycine, allo-threonine, serine, aspartic acid, beta-cyano alanine andvaline side chains;

[0071] R¹′ and R¹″ independently represent hydrogen and radicals asdefined for R¹, or one of R¹′ and R¹″, together with R¹ and the carbonatoms to which R¹, R¹ and R¹″ are attached, represent a cycloalkylradical;

[0072] R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl andaralkyl radicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —C≡N, CF₃, —OR⁹ and —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals;

[0073] R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

[0074] R⁴ represents radicals as defined by R³.

[0075] A more preferred family of compounds within Formula IV consistsof compounds wherein

[0076] R represents an arylalkanoyl, heteroaroyl, aryloxyalkanoyl,aryloxycarbonyl, alkanoyl, aminocarbonyl, mono-substitutedaminoalkanoyl, or disubstituted aminoalkanoyl, or mono-ordialkylaminocarbonyl radical;

[0077] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

[0078] R¹, R¹′ and R¹″ independently represent hydrogen and alkylradicals having from 1 to about 4 carbon atoms, alkenyl, alkynyl,aralkyl radicals, and radicals represented by the formula —CH₂C(O)R″ or—C(O)R″ wherein R″ represents R³⁸, —NR³⁸R³⁹ and OR³⁸ wherein R³⁸ and R³⁹independently represent hydrogen and alkyl radicals having from 1 toabout 4 carbon atoms;

[0079] R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl radicals; and

[0080] R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals.

[0081] Of highest interest are compounds of Formula IV wherein:

[0082] R represents an arylalkanoyl, aryloxycarbonyl, aryloxyalkanoyl,alkanoyl, aminocarbonyl, mono-substituted aminoalkanoyl, ordisubstituted aminoalkanoyl, or mono-or dialkylaminocarbonyl radical;

[0083] R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

[0084] R¹, R¹ and R¹ independently represent hydrogen, methyl, ethyl,benzyl, phenylpropyl and propargyl radicals;

[0085] R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl,4-fluorobenzyl, 2-naphthylmethyl and cyclohexylmethyl radicals;

[0086] R³ represents alkyl, cyclohexyl, isobutyl, isoamyl and n-butylradicals; and

[0087] R⁴ represents methyl, phenyl and substituted phenyl radicalswherein the substituents are selected from halo, alkoxy, amino and nitrosubstituents.

[0088] As utilized herein, the term “alkyl”, alone or in combination,means a straight-chain or branched-chain alkyl radical containing from 1to about 10 carbon atoms, preferably from 1 to about 8 carbon atoms,more preferably 1-5 carbon atoms. Examples of such radicals includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. The term“alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radial having one or more double bonds andcontaining from 2 to about 18 carbon atoms, preferably from 2 to about 8carbon atoms, more preferably from 2 to about 5 carbon atoms. Examplesof suitable alkenyl radicals include ethenyl, propenyl, alkyl,1,4-butadienyl and the like. The term “alkynyl”, alone or incombination, means a straight-chain or branched chain hydrocarbonradical having one or more triple bonds and containing from 2 to about10 carbon atoms, more preferably from 2 to about 5 carbon atoms.Examples of alkynyl radicals include ethynyl, propynyl, (propargyl),butynyl and the like. The term “alkoxy”, alone or in combination, meansan alkyl ether radical wherein the term alkyl is as defined above.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy andthe like. The term “cycloalkyl”, alone or in combination, means asaturated or partially saturated monocyclic, bicyclic or tricyclic alkylradical wherein each cyclic moiety contains from about 3 to about 8carbon atoms, more preferably from about 3 to about 6 carbon atoms, andis cyclic. Examples of such cycloalkyl radicals include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like. The term“cycloalkylalkyl” means an alkyl radical as defined above which issubstituted by a cycloalkyl radical as defined above. The term “aryl”,alone or in combination, means a phenyl or naphthyl radical whichoptionally carries one or more substituents selected from alkyl, alkoxy,halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy,alkoxycarbonyl, cycloalkyl, heterocycloalkyl, amido, mono and dialkylsubstituted amino, mono and dialkyl substituted amido and the like, suchas phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl,and the like. The terms “aralkyl” and “aralkoxy”, alone or incombination, means an alkyl or alkoxy radical as defined above in whichat least one hydrogen atom is replaced by an aryl radical as definedabove, such as benzyl, benzyloxy, 2-phenylethyl, dibenzylmethyl,hydroxyphenylmethyl, methylphenylmethyl, and the like. The term“aralkoxy carbonyl”, alone or in combination, means a radical of theformula —C(O)—O-aralkyl in which the term “aralkyl”, has thesignificance given above. Examples of an aralkoxycarbonyl radical arebenzyloxycarbonyl and methylphenylmethoxycarbonyl. The term “aryloxy”means a radical of the formula aryl —O— in which the term aryl has thesignificance given above. The term “alkanoyl”, alone or in combination,means an acyl radical derived from an alkanecarboxylic acid, examples ofwhich include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, andthe like. The term “cycloalkylcarbonyl” means an acyl group derived froma monocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term “aralkanoyl” meansan acyl radical derived from an aryl-substituted alkanecarboxylic acidsuch as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like. The term“aroyl” means an acyl radical derived from an aromatic carboxylic acid.Examples of such radicals include aromatic carboxylic acids, anoptionally substituted benzoic or naphthoic acid such as benzoyl,4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl,1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The terms “heterocyclyl” and “heterocycloalkyl” alone or in combination,mean a saturated or partially unsaturated monocyclic, bicyclic ortricyclic heterocycle which contains one or more heteroatoms selectedfrom nitrogen, oxygen and sulphur, which is optionally substituted onone or more carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl,aralkyl and the like, and/or on a secondary nitrogen atom (i.e., —NH—)by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyland/or on a tertiary nitrogen atom (i.e. ═N—) by oxido and which isattached via a carbon atom. Heterocycloalkyl and heterocyclyl alsoincludes benz-fused monocyclic cycloalkyl groups having at least oneheteroatom. Heterocycloalkyl and heterocyclyl in addition to sulfur andnitrogen also includes sulfones, sulfoxides and N-oxides of tertiarynitrogen containing heterocycloalkyl groups. The term “heteroaryl”,alone or in combination, means-an aromatic monocyclic, bicyclic, ortricyclic heterocycle which contains the heteroatoms and is optionallysubstituted as defined above with respect to the definitions of aryl andheterocycloalkyl. Examples of such heterocycloalkyl and heteroarylgroups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, (e.g.,2-(1-piperidinyl)pyridyl and 2-(4-benzyl piperazin-1-yl-1-pyridinyl),pyrazinyl, pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl,indolyl (e.g., 2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl,3-quinolinyl, 1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g.,1-isoquinolinyl, 3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-, 2-,4- or 5-benzimidazolyl, andthe like. The term “cycloalkylalkoxycarbonyl” means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl-O—COOH wherein cycloalkylalkyl has the significancegiven above. The term “aryloxyalkanoyl” means an acyl radical of theformula aryl-O-alkanoyl wherein aryl and alkanoyl have the significancegiven above. The term “heterocycloalkoxycarbonyl” means an acyl groupderived from heterocyclyl-O—COOH wherein heterocyclyl is as definedabove. The term “heterocycloalkylalkanoyl” is an acyl radical derivedfrom a heterocycloalkyl-substituted alkane carboxylic acid whereinheterocycloalkyl has the significance given above. The term“heterocycloalkylalkoxycarbonyl” means an acyl radical derived from aheterocycloalkyl-substituted alkane-O—COOH wherein heterocyclyl has thesignificance given above. The term “heteroaryloxycarbonyl” means an acylradical derived from a carboxylic acid represented by heteroaryl-O—COOHwherein heteroaryl has the significance given above. The term“aminocarbonyl” alone or in combination, means an amino-substitutedcarbonyl (carbamoyl) group wherein the amino group can be a primary,secondary or tertiary amino group containing substituents selected fromalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.The term “aminoalkanoyl” means an acyl group derived from anamino-substituted alkanecarboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like. The term “halogen” means fluorine, chlorine, bromine oriodine. The term “haloalkyl” means an alkyl radical having thesignificance as defined above wherein one or more hydrogens are replacedwith a halogen. Examples of such haloalkyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term “leavinggroup” generally refers to groups readily displaceable by a nucleophile,such as an amine, a thiol or an alcohol nucleophile. Such leaving groupsare well known in the art. Examples of such leaving groups include, butare not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole,halides, triflates, tosylates and the like. Preferred leaving groups areindicated herein where appropriate. The term “amino acid side chain”means the side chain group, including the stereochemistry of the carbonto which it is attached, attached to the naturally occurring amino acidwhich distinguishes the amino acid from glycine. For example, the aminoacid side chain of alanine is methyl, of histidine is imidazolylmethyland phenylalanine is benzyl, and the attachment of such side chains tothe compound of this invention retain the naturally occurringstereochemistry of the carbon to which it is attached. The followingexample illustrates the definitions:

[0089] Procedures for preparing the compounds of Formula I are set forthbelow. It should be noted that the general procedure is shown as itrelates to preparation of compounds having the specifiedstereochemistry, for example, wherein the absolute stereochemistry aboutthe hydroxyl group is designated as (R). However, such procedures aregenerally applicable to those compounds of opposite configuration, e.g.,where the stereochemistry about the hydroxyl group is (S). In addition,the compounds having the (R) stereochemistry can be utilized to producethose having the (S) stereochemistry. For example, a compound having the(R) stereochemistry can be inverted to the (S) stereochemistry usingwell-known methods.

Preparation of Compounds of Formula I

[0090] The compounds of the present invention represented by Formula Iabove can be prepared utilizing the following general procedure. Thisprocedure is schematically shown in the following Schemes I and II:

[0091] a) amine b) sulfonyl chloride R⁴SO₂Cl (or anhydride)+acidscavenger c) deprotection d) coupling e) coupling.

[0092] a) amine b) sulfonyl chloride R⁴SO₂Cl (or anhydride)+acidscavenger c) deprotection d) coupling e) coupling.

[0093] An N-protected chloroketone derivative of an amino acid havingthe formula:

[0094] wherein P represents an amino protecting group, and R² is asdefined above, is reduced to the corresponding alcohol utilizing anappropriate reducing agent. Suitable amino protecting groups are wellknown in the art and include carbobenzoxy, t-butoxycarbonyl, and thelike. A preferred amino protecting group is carbobenzoxy. A preferredN-protected chloroketone is N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone. A preferred reducing agent is sodium borohydride.The reduction reaction is conducted at a temperature of from −10° C. toabout 25° C., preferably at about 0° C., in a suitable solvent systemsuch as, for example, tetrahydrofuran, and the like. The N-protectedchloroketones are commercially available, e.g., such as from Bachem,Inc., Torrance, Calif. Alternatively, the chloroketones can be preparedby the procedure set forth in S. J. Fittkau, J. Prakt. Chem., 315, 1037(1973), and subsequently N-protected utilizing procedures which are wellknown in the art.

[0095] The halo alcohol can be utilized directly, as described below,or, preferably, is then reacted, preferably at room temperature, with asuitable base in a suitable solvent system to produce an N-protectedamino epoxide of the formula:

[0096] wherein P and R² are as defined above. Suitable solvent systemsfor preparing the amino epoxide include ethanol, methanol, isopropanol,tetrahydrofuran, dioxane, and the like including mixtures thereof.Suitable bases for producing the epoxide from the reduced chloroketoneinclude potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBUand the like. A preferred base is potassium hydroxide.

[0097] Alternatively, a protected amino epoxide can be prepared, such asin co-owned and co-pending PCT Patent Application Serial No.PCT/US93/04804 whcih is incorporated herein by reference, starting withan L-amino acid which is reacted with a suitable amino-protecting groupin a suitable solvent to produce an amino-protected L-amino acid esterof the formula:

[0098] wherein P³ represents carboxyl-protecting group, e.g., methyl,ethyl, benzyl, tertiary-butyl and the like; R² is as defined above; andp¹ and p² independently are selected from amine protecting groups,including but not limited to, arylalkyl, substituted arylalkyl,cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substitutedallyl, acyl, alkoxycarbonyl, aralkoxycarbonyl and silyl. Examples ofarylalkyl include, but are not limited to benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl of C₁-C₈, alkoxy, hydroxy, nitro, alkylene, amino, alkylamino,acylamino and acyl, or their salts, such as phosphonium and ammoniumsalts. Examples of aryl groups include phenyl, naphthalenyl, indanyl,anthracenyl, durenyl, 9-(9-phenylfluorenyl) and phenanthrenyl,cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals containingcycloalkyls of C₆-C₁₀. Suitable acyl groups include carbobenzoxy,t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl,butyryl, acetyl, tri-fluoroacetyl, trichloroacetyl, phthaloyl and thelike.

[0099] Additionally, the p¹ and/or p² protecting groups can form aheterocyclic ring with the nitrogen to which they are attached, forexample, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl,maleimidyl and the like and where these heterocyclic groups can furtherinclude adjoining aryl and cycloalkyl rings. In addition, theheterocyclic groups can be mono-, di- or tri-substituted, e.g.,nitrophthalimidyl. The term silyl refers to a silicon atom optionallysubstituted by one or more alkyl, aryl and aralkyl groups.

[0100] Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of the amine functions to provide mono-or bis-disilylamine can provide derivatives of the aminoalcohol, aminoacid, amino acid esters and amino acid amide. In the case of aminoacids, amino acid esters and amino acid amides, reduction of thecarbonyl function provides the required mono- or bis-silyl aminoalcohol.Silylation of the aminoalcohol can lead to the N,N,O-tri-silylderivative. Removal of the silyl function from the silyl ether functionis readily accomplished by treatment with, for example, a metalhydroxide or ammonium flouride reagent, either as a discrete reactionstep or in situ during the preparation of the amino aldehyde reagent.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chlorie,diphenylmethylsilyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

[0101] Preferably P¹ and P² are independently selected from aralkyl andsubstituted aralkyl. More preferably, each of P¹ and P² is benzyl.

[0102] The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at −78° C. in asuitable solvent such as toluene. Preferred reducing agents includelithium aluminium hydride, lithium borohydride, sodium borohydride,borane, lithium tri-terbutoxyaluminum hydride, borane/THF complex. Mostpreferably, the reducing agent is diisobutylaluminum hydride (DiBAL-H)in toluene. The resulting alcohol is then converted, for example, by wayof a Swern oxidation, to the corresponding aldehyde of the formula:

[0103] wherein P¹, P² and R² are as defined above. Thus, adichloromethane solution of the alcohol is added to a cooled (−75 to−68° C.) solution of oxalyl chloride in dichloromethane and DMSO indichloromethane and stirred for 35 minutes.

[0104] Acceptable oxidizing reagents include, for example, sulfurtrioxide-pyridine complex and DMSO, oxalyl chloride and DMSO, acetylchloride or anhydride and DMSO, trifluoroacetyl chloride or anhydrideand DMSO, methanesulfonyl chloride and DMSO ortetrahydrothiaphene-S-oxide, toluenesulfonyl bromide and DMSO,trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO,phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSOand isobutylchloroformate and DMSO. The oxidation conditions reported byReetz et al [Anaew Chem., 99, p. 1186, (1987)], Anaew Chem. Int. Ed.Enal., 26, p. 1141, 1987) employed oxalyl chloride and DMSO at −78° C.

[0105] The preferred oxidation method described in this invention issulfur trioxide pyridine complex, triethylamine and DMSO at roomtemperature. This system provides excellent yields of the desired chiralprotected amino aldehyde usable without the need for purification i.e.,the need to purify kilograms of intermediates by chromatography iseliminated and large scale operations are made less hazardous. Reactionat room temperature also eliminated the need for the use of lowtemperature reactor which makes the process more suitable for commercialproduction.

[0106] The reaction may be carried out under and inert atmosphere suchas nitrogen or argon, or normal or dry air, under atmospheric pressureor in a sealed reaction vessel under positive pressure. Preferred is anitrogen atmosphere. Alternative amine bases include, for example,tri-butyl amine, tri-isopropyl amine, N-methylpiperidine, N-methylmorpholine, azabicyclononane, diisopropylethylamine,2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine, or mixtures ofthese bases. Triethylamine is a preferred base. Alternatives to pureDMSO as solvent include mixtures of DMSO with non-protic or halogenatedsolvents such as tetrahydrofuran, ethyl acetate, toluene, xylene,dichloromethane, ethylene dichloride and the like. Dipolar aproticco-solvents include acetonitrile, dimethylformamide, dimethylacetamide,acetamide, tetramethyl urea and its cyclic analog, N-methylpyrrolidone,sulfolane and the like. Rather than N,N-dibenzylphenylalaninol as thealdehyde precursor, the phenylalaninol derivatives discussed above canbe used to provide the corresponding N-monosubstituted [either P¹ orP²=H] or N,N-disubstituted aldehyde.

[0107] In addition, hydride reduction of an amide or ester derivative ofthe corresponding alkyl, benzyl or cycloalkenyl nitrogen protectedphenylalanine, substituted phenylalanine or cycloalkyl analog ofphenyalanine derivative can be carried out to provide the aldehydes.Hydride transfer is an additional method of aldehyde synthesis underconditions where aldehyde condensations are avoided, cf, OppenauerOxidation.

[0108] The aldehydes of this process can also be prepared by methods ofreducing protected phenylalanine and phenylalanine analogs or theiramide or ester derivatives by, e.g., sodium amalgam with HCl in ethanolor lithium or sodium or potassium or calcium in ammonia. The reactiontemperature may be from about −20° C. to about 45° C., and preferablyfrom abut 5° C. to about 25° C. Two additional methods of obtaining thenitrogen protected aldehyde include oxidation of the correspondingalcohol with bleach in the presence of a catalytic amount of2,2,6,6-tetramethyl-1-pyridyloxy free radical. In a second method,oxidation of the alcohol to the aldehyde is accomplished by a catalyticamount of tetrapropylammonium perruthenate in the presence ofN-methylmorpholine-N-oxide.

[0109] Alternatively, an acid chloride derivative of a protectedphenylalanine or phenylalanine derivative as disclosed above can bereduced with hydrogen and a catalyst such as Pd on barium carbonate orbarium sulphate, with or without an additional catalyst moderating agentsuch as sulfur or a thiol (Rosenmund Reduction).

[0110] The aldehyde resulting from the Swern oxidation is then reactedwith a halomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹CH₂X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to −78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas:

[0111] The diastereomers can be separated e.g., by chromatography, or,alternatively, once reacted in subsequent steps the diastereomericproducts can be separated. For compounds having the (S) stereochemistry,a D-amino acid can be utilized in place of the L-amino acid.

[0112] The addition of chloromethylithium or bromomethylithium to achiral amino aldehyde is highly diastereoselective. Preferably, thechloromethyllithium or bromomethylithium is generated in-situ from thereaction of the dihalomethane and n-butyllithium. Acceptablemethyleneating halomethanes include chloroiodomethane,bromochloromethane, dibromomethane, diiodomethane, bromofluoromethaneand the like. The sulfonate ester of the addition product of, forexample, hydrogen bromide to formaldehyde is also a methyleneatingagent. Tetrahydrofuran is the preferred solvent, however alternativesolvents such as toluene, dimethoxyethane, ethylene dichloride,methylene chloride can be used as pure solvents or as a mixture. Dipolaraprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone areuseful as solvents or as part of a solvent mixture. The reaction can becarried out under an inert atmosphere such as nitrogen or argon. Forn-butyl lithium can be substituted other organometalic reagents reagentssuch as methyllithium, tert-butyl lithium, sec-butyl lithium,phenyllithium, phenyl sodium and the like. The reaction can be carriedout at temperatures of between about −80° C. to 0° C. but preferablybetween about −80° C. to −20° C. The most preferred reactiontemperatures are between −40° C. to −15° C. Reagents can be added singlybut multiple additions are preferred in certain conditions. Thepreferred pressure of the reaction is atmospheric however a positivepressure is valuable under certain conditions such as a high humidityenvironment.

[0113] Alternative methods of conversion to the epoxides of thisinvention include substitution of other charged methylenation precurserspecies followed by their treatment with base to form the analogousanion. Examples of these species include trimethylsulfoxonium tosylateor triflate, tetramethylammonium halide, methyldiphenylsulfoxoniumhalide wherein halide is chloride, bromide or iodide.

[0114] The conversion of the aldehydes of this invention into theirepoxide derivative can also be carried out in multiple steps. Forexample, the addition of the anion of thioanisole prepared from, forexample, a butyl or aryl lithium reagent, to the protectedaminoaldehyde, oxidation of the resulting protected aminosulfide alcoholwith well known oxidizing agents such as hydrogen peroxide, tert-butylhypochlorite, bleach or sodium periodate to give a sulfoxide. Alkylationof the sulfoxide with, for example, methyl iodide or bromide, methyltosylate, methyl mesylate, methyl triflate, ethyl bromide, isopropylbromide, benzyl chloride or the like, in the presence of an organic orinorganic base Alternatively, the protected aminosulfide alcohol can bealkylated with, for example, the alkylating agents above, to provide asulfonium salts that are subsequently converted into the subjectepoxides with tert-amine or mineral bases.

[0115] The desired epoxides formed, using most preferred conditions,diastereoselectively in ratio amounts of at least about an 85:15 ratio(S:R). The product can be purified by chromatography to give thediastereomerically and enantiomerically pure product but it is moreconveniently used directly without purification to prepare retroviralprotease inhibitors. The foregoing process is applicable to mixtures ofoptical isomers as well as resolved compounds. If a particular opticalisomer is desired, it can be selected by the choice of startingmaterial, e.g., L-phenylalanine, D-phenylalanine, L-phenylalaninol,D-phenylalaninol, D-hexahydrophenylalaninol and the like, or resolutioncan occur at intermediate or final steps. Chiral auxiliaries such as oneor two equivilants of camphor sulfonic acid, citric acid, camphoricacid, 2-methoxyphenylacetic acid and the like can be used to form salts,esters or amides of the compounds of this invention. These compounds orderivatives can be crystallized or separated chromatographically usingeither a chiral or achiral column as is well known to those skilled inthe art.

[0116] The amino epoxide is then reacted, in a suitable solvent system,with an equal amount, or preferably an excess of, a desired amine of theformula:

R³NH₂

[0117] wherein R³ is hydrogen or is as defined above. The reaction canbe conducted over a wide range of temperatures, e.g., from about 10° C.to about 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic organic solventssuch as, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Exemplary amines corresponding to theformula R³NH₂ include benzyl amine, isobutylamine, n-butyl amine,isopentyl amine, isoamylamine, cyclohexanemethyl amine, naphthylenemethyl amine and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-(NHR³)-propan-2-ol derivative (hereinafter referred toas an amino alcohol) can be represented by the formulas:

[0118] wherein P, P¹, P², R² and R³ are as described above.Alternatively, a haloalcohol can be utilized in place of the aminoepoxide.

[0119] The amino alcohol defined above is then reacted in a suitablesolvent with a sulfonyl chloride (R⁴SO₂Cl) or sulfonyl anhydride in thepresence of an acid scavenger. Suitable solvents in which the reactioncan be conducted include methylene chloride, tetrahydrofuran. Suitableacid scavengers include triethylamine, pyridine. Preferred sulfonylchlorides are methanesulfonyl chloride and benzenesulfonyl chloride. Theresulting sulfonamide derivative can be represented, depending on theepoxide utilized by the formulas

[0120] wherein P, P¹, P², R², R³ and R⁴ are as defined above. Theseintermediates are useful for preparing inhibitor compounds of thepresent invention and are also active inhibitors of retroviralproteases.

[0121] The sulfonyl halides of the formula R⁴SO₂X can be prepared by thereaction of a suitable Grignard or alkyl lithium reagent with sulfurylchloride, or sulfur dioxide followed by oxidation with a halogen,preferably chlorine. Also, thiols may be oxidized to sulfonyl chloridesusing chlorine in the presence of water under carefully controlledconditions. Additionally, sulfonic acids may be converted to sulfonylhalides using reagents such as PCl₅, and also to anhydrides usingsuitable dehydrating reagents. The sulfonic acids may in turn beprepared using procedures well known in the art. Such sulfonic acids arealso commercially available. In place of the sulfonyl halides, sulfinylhalides (R⁴SOX) or sulfenyl halides (R⁴SX) can be utilized to preparecompounds wherein the —SO₂— moiety is replaced by an —SO— or —S— moiety,respectively.

[0122] Following preparation of the sulfonamide derivative, the aminoprotecting group P or P¹ and P² amino protecting groups are removedunder conditions which will not affect the remaining portion of themolecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. A preferred method involvesremoval of the protecting group, e.g., removal of a carbobenzoxy group,by hydrogenolysis utilizing palladium on carbon in a suitable solventsystem such as an alcohol, acetic acid, and the like or mixturesthereof. Where the protecting group is a t-butoxycarbonyl group, it canbe removed utilizing an inorganic or organic acid, e.g., HCl ortrifluoroacetic acid, in a suitable solvent system, e.g., dioxane ormethylene chloride. The resulting product is the amine salt derivative.Following neutralization of the salt, the amine is then reacted with anamino acid or corresponding derivative thereof represented by theformula (PN[CR¹′ R¹″]_(t) CH(R¹)COOH) wherein t, R¹, R¹′ and R¹″ are asdefined above, to produce the antiviral compounds of the presentinvention having the formula:

[0123] wherein t, P, R¹, R¹′, R¹″, R², R³ and R⁴ are as defined above.Preferred protecting groups in this instance are a benzyloxycarbonylgroup or a t-butoxycarbonyl group. Where t is 0 and R¹ is alkyl,alkenyl, alkynyl, cycloalkyl, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂[S(O)CH₃],—C(CH₃)₂[S(O₂)CH₃], or an amino acid side chain, such materials are wellknown and many are commercially available from Sigma-Aldrich.

[0124] Where the amine is reacted with a derivative of an amino acid,e.g., when t=1, so that the amino acid is a β-amino acid, such β-aminoacids can be prepared according to the procedure set forth in aco-owned, copending patent application, U.S. Ser. No. 07/853,561 or thefollowing procedures.

[0125] Various methods have been proposed for the preparation of chiralβ-amino acids. See, for example, Chemistry and Biochemistry of AminoAcids, Vol. 4, Chapter 5, pp. 250-57, B. Weinstein, Ed., Dekker, N.Y.(1975). Furukawa et al, Chem. Pharm. Bull., 25, 1319 (1977), discloseasymmetric synthesis of β-amino acids by addition of chiral amines tocarbon-carbon double bonds having nitrile or ester groups in theα-position. However, optical purities of the β-amino acids thus producedrange from 2 to 19%. Furukawa et al also report that optically activeβ-amino acids have been produced with optical purities ranging from 2 to28% by reacting chiral Schiff bases with Reformsky reagent. Terentev etal, Dohl. Ahad. Nauh SSR, 163,674 (1965) disclose synthesis ofβ-aminobutyric acids involving addition of chiral amines to crotonicacid with optical purities ranging from 7-9%.

[0126] Brown et al, Tetrahedron Lett., Vol. 28, No. 19, pp 2179-2182(1987), disclose a method of preparing optically active disubstitutedβ-amino acids which involves asymmetric catalytic hydrogenation ofN-substituted α-(aminoalkyl) acrylates. In order to verify thestereochemistry of the product, Curtius rearrangement was effected onthe monomethyl ester of optically enriched RR-anti-2,3-dimethyl-succinicacid and trapping of the incipient isocyanate derivative with tertiaryalcohol, namely, t-butyl alcohol, to give the corresponding R-enrichedβ-amino acid.

[0127] Ninomita et al, Tetrahedron Lett., Vol. 30, 2152-2157 (1975)studied the Curtius rearrangement utilizing benzoic acid,diphenylphosphoryl azide and triethylamine followed by treatment withvarious alcohols and found that t-butyl alcohol gives yields superior tobenzyl alcohol, ethanol and phenol.

[0128] Utilization of a primary or secondary alcohol to trap anisocyanate derivative of a chiral mono-substituted succinate, and, inparticular, in a Curtius rearrangement of a chiral mono-substitutedsuccinate, to produce chiral β-amino acids significantly increases theoverall yield. The resulting carbamate-protected β-amino esters are thensaponified to produce the corresponding carbamate-protected β-aminoacids which are then deprotected to produce β-amino acids possessing thesame absolute configuration as naturally-occurring (L)-amino acids.

[0129] The overall reaction sequence can be shown as follows:

[0130] wherein R¹, R¹′, R¹″, and P are as defined above and P⁴OH arepreferably represents radicals derived from primary and secondaryalcohols.

[0131] This process can also be used in the asymetric synthesis ofβ-amino acids represented by the formula:

[0132] wherein R¹, R¹′ and R¹″ are as defined above. Such compounds areformed by Curtius rearrangement of 2(R)-substituted succinatesrepresented by the formula

[0133] wherein R¹, R¹′, R¹″ and P are as defined above, to afford theisocyanate derivative:

[0134] Using 2(S)-substituted succinates, 2(S)-substituted β-amino acidscan also be prepared stereospecifically.

[0135] Curtius rearrangement involves pyrolysis of acyol azides

[0136] to yield isocyanates (R—N═C═O) which can be subsequentlyhydrolyzed to give amines. See March, Advanced Organic Chemistry, p.1005, 2nd ed (1977). As a general rule, Curtius rearrangement is aconcerted reaction and therefore proceeds with retention ofconfiguration of the starting materials. Determination of specificreaction conditions for effecting Curtius rearrangements of varioussuccinates is within the skill of one in the art familiar with suchreactions. In the method of the present invention, Curtius rearrangementto afford the desired isocyante is preferably effected by treating a2-substituted succinate with one equivalent of diphenoxyphosphoryl azide(PhO)₂PON₃ and triethylamine to form the acyl azide followed by heatingin an inert solvent, such as in warm toluene, preferably at about 80° C.for about three hours, to afford the isocyante derivative.

[0137] Suitable primary and secondary alcohols include those representedby the formula P⁴OH where P⁴ representes substituted and unsubstitutedalkyl, cycloalkyl, aralkyl and aryl radicals, as well as suitableequivalents such as, for example, silyl radicals. Preferably, theprimary and secondary alcohols are those wherein P⁴ representssubstituted and unsubstituted, straight chain as well as branched chain,alkyl radicals having from 1 to about 12 carbon atoms, substituted andunsubstituted cycloalkyl radicals having from 4 to about 7 carbon atoms,and substituted and unsubstituted aryl, alkaryl and aralkyl radicals.Examples of such suitable alcohols include benzyl alcohol, isopropylalcohol, 4-methoxybenzyl alcohol, 2-trimethylsilylethanol, fluorenylmethanol and benzhydrol. Preferred alcohols are benzyl alcohol and4-methoxybenzyl alcohol. Other primary and secondary alcohols suitablefor use in the practice of the present invention will be readilyapparent to those skilled in the art.

[0138] The ester derivative is then saponified by any one of numerouswell-known procedures, such as by treatment with aqueous lithiumhydroxide/THF (tetrahydrofuran), preferably for three hours at 0° C. Theresultant product is the corresponding carbamate-protected β-aminoacids. These are subsequently deprotected by any one of severalwell-known procedures, such as by acid catalyzed hydrolysis or byhydrogenolysis, to produce the corresponding deprotected β-amino acids.Alternatively, the carbamate-protected β-amino acid can be coupled tothe amine

[0139] followed by deprotection and incorporation of R and R′.

[0140] The N-protecting group can be subsequently removed, if desired,utilizing the procedures described above, and then reacted with acarboxylate represented by the formula:

[0141] wherein R is as defined above and L is an appropriate leavinggroup such as a halide. Preferably, where R¹ is a side chain of anaturally occurring α-amino acid, R is a 2-quinoline carbonyl groupderived from N-hydroxysuccinimide-2-quinoline carboxylate, i.e., L ishydroxy succinimide. A solution of the free amine (or amine acetatesalt) and about 1.0 equivalent of the carboxylate are mixed in anappropriate solvent system and optionally treated with up to fiveequivalents of a base such as, for example, N-methylmorpholine, at aboutroom temperature. Appropriate solvent systems include tetrahydrofuran,methylene chloride or N,N-dimethylformamide, and the like, includingmixtures thereof.

[0142] Alternatively, the protected amino alcohol from the epoxideopening can be further protected at the newly introduced amino groupwith a protecting group PI which is not removed when the firstprotecting P is removed. One skilled in the art can choose appropriatecombinations of P and P′. One suitable choice is when P is Cbz and P′ isBoc. The resulting compound represented by the formula:

[0143] can be carried through the remainder of the synthesis to providea compound of the formula:

[0144] and the new protecting group P′ is selectively removed, andfollowing deprotection, the resulting amine reacted to form thesulfonamide derivative as described above. This selective deprotectionand conversion to the sulfonamide can be accomplished at either the endof the synthesis or at any appropriate intermediate step if desired.

[0145] The thiocarbonyl compounds of this invention are really preparedby methods well known to those skilled in the art, for example, bytreatment of a carbonyl compound with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)which is an article of commerce. Phosphoruspentasulfide may also be usedor one can treat an amine of this invention with a pre-formedthiocarbonyl reagent such as thiocarbonylchlorid in the presence ofbase.

[0146] In place of the sulfonyl halides, sulfinyl halides (RSOCl) andsulfenyl halides (RSCl) can be utilized to prepare compounds wherein the—SO₂— moiey is replaced by —SO— or —S—, respectively.

[0147] It is contemplated that for preparing compounds of the Formulashaving R⁶, the compounds can be prepared following the procedure setforth above and, prior to coupling the sulfonamide derivative or analogthereof, e.g. coupling to the amino acid PNH(CH₂)_(t)CH(R¹)COOH, carriedthrough a procedure referred to in the art as reductive amination. Thus,a sodium cyanoborohydride and an appropriate aldehyde or ketone can bereacted with the sulfonamide derivative compound or appropriate analogat room temperature in order to reductively aminate any of the compoundsof Formulas I-IV. It is also contemplated that where R³ of the aminoalcohol intermediate is hydrogen, the inhibitor compounds of the presentinvention wherein R³ is alkyl, or other substituents wherein the α-Ccontains at least one hydrogen, can be prepared through reductiveamination of the final product of the reaction between the amino alcoholand the amine or at any other stage of the synthesis for preparing theinhibitor compounds.

[0148] Contemplated equivalents of the general formulas set forth abovefor the antiviral compounds and derivatives as well as the intermediatesare compounds otherwise corresponding thereto and having the samegeneral properties, such as tautomers thereof as well as compounds,wherein one or more of the various R groups are simple variations of thesubstituents as defined therein, e.g., wherein R is a higher alkyl groupthan that indicated. In addition, where a substituent is designated as,or can be, a hydrogen, the exact chemical nature of a substituent whichis other than hydrogen at that position, e.g., a hydrocarbyl radical ora halogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure.

[0149] The chemical reactions described above are generally disclosed interms of their broadest application to the preparation of the compoundsof this invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

[0150] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0151] All reagents were used as received without purification. Allproton and carbon NMR spectra were obtained on either a Varian VXR-300or VXR-400 nuclear magnetic resonance spectrometer.

[0152] The following Examples 1 through 9 illustrate preparation ofintermediates. These intermediates are useful in preparing the inhibitorcompounds of the present invention as illustrated in Examples 10-16. Inaddition, the intermediates of Examples 2-6 are also retroviral proteaseinhibitors and inhibit, in particular, HIV protease.

EXAMPLE 1A

[0153]

[0154] Preparation ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isoamylamine

[0155] Part A:

[0156] To a solution of 75.0 g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. 1 L). Thesolution was washed sequentially with 1M potassium hydrogen sulfate,saturated sodium bicarbonate and then saturated sodium chloridesolutions. After drying over anhydrous magnesium sulfate and filtering,the solution was removed under reduced pressure. To the resulting oilwas added hexane (approx. 1 L) and the mixture warmed to 60° C. withswirling. After cooling to room temperature, the solids were collectedand washed with 2 L of hexane. The resulting solid was recrystallizedfrom hot ethyl acetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

[0157] Part B:

[0158] To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassiumhydroxide in 968 mL of absolute ethanol at room temperature, was added32.3 g (0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol.After stirring for fifteen minutes, the solvent was removed underreduced pressure and the solids dissolved in methylene chloride. Afterwashing with water, drying over magnesium sulfate, filtering andstripping, one obtains 27.9 g of a white solid. Recrystallization fromhot ethyl acetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102-103°C. and MH⁺ 298.

[0159] Part C:

[0160] A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (1.00 g, 3.36 mmol) andisoamylamine (4.90 g, 67.2 mmol, 20 equiv.) in 10 mL of isopropylalcohol was heated to reflux for 1.5 hours. The solution was cooled toroom temperature, concentrated in vacuo and then poured into 100 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN=[[3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl]N-[(3-methylbutyl)]aminemp 108.0-109.5° C., MH⁺ m/z=371.

EXAMPLE 1B

[0161]

[0162] Preparation ofN,N-dibenzyl-3(S)-amino-1.2-(S)-epoxy-4-phenylbutane

[0163] Step A:

[0164] A solution of L-phenylalanine (50.0 g, 0.302 mol), sodiumhydroxide (24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605mol) in water (500 ml) was heated to 97° C. Benzyl bromide (108.5 ml,0.912 mol) was then slowly added (addition time—25 min). The mixture wasthen stirred at 97°c for 30 minutes. The solution was cooled to roomtemperature and extracted with toluene (2×250 ml). The combined organiclayers were then washed with water, brine, dried over magnesium sulfate,filtered and concentrated to give an oil product. The crude product wasthen used in the next step without purification.

[0165] Step B:

[0166] The crude benzylated product of the above step was dissolved intoluene (750 ml) and cooled to −55° C. A 1.5 M solution of DIBAL-H intoluene (443.9 ml, 0.666 mol) was then added at a rate to maintain thetemperature between −55° to −50° C. (addition time—1 hour). The mixturewas stirred for 20 minutes at −55° C. The reaction was quenched at −55°C. by the slow addition of methanol (37 ml). The cold solution was thenpoured into cold (5° C.) 1.5 N HCl solution (1.8 L). The precipitatedsolid (approx. 138 g) was filtered off and washed with toluene. Thesolid material was suspended in a mixture of toluene (400 ml) and water(100 ml). The mixture was cooled to 5° C., treated with 2.5 N NaOH (186ml) and then stirred at room temperature until the solid was dissolved.The toluene layer was separated from the aqueous phase and washed withwater and brine, dried over magnesium sulfate, filtered and concentratedto a volume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml)were then added to the residue upon which the alcohol product began tocrystallize. After 30 min., an additional 50 ml hexane was added topromote further crystallization. The solid was filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof material could be isolated by refiltering the mother liquor. Thesolids were combined and recrystallized from ethyl acetate (20 ml) andhexane (30 ml) to give, in 2 crops, approximately 40 g (40% fromL-phenylalanine) of analytically pure alcohol product. The motherliquors were combined and concentrated (34 g). The residue was treatedwith ethyl acetate and hexane which provided an additional 7 g (−7%yield) of slightly impure solid product. Further optimization in therecovery from the mother liquor is probable.

[0167] Alternatively, the alcohol was prepared from L-phenylalaninol.L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirred solution ofpotassium carbonate (484.6 g, 3.506 mol) in 710 mL of water. The mixturewas heated to 65° C. under a nitrogen atmosphere. A solution of benzylbromide (400 g, 2.339 mol) in 3A ethanol (305 mL) was added at a ratethat maintained the temperature between 60-68° C. The biphasic solutionwas stirred at 65° C. for 55 min and then allowed to cool to 10° C. withvigorous stirring. The oily product solidified into small granules. Theproduct was diluted with 2.0 L of tap water and stirred for 5 minutes todissolve the inorganic by products. The product was isolated byfiltration under reduced pressure and washed with water until the pH is7. The crude product obtained was air dried overnite to give a semi-drysolid (407 g) which was recrystallized from 1.1 L of ethylacetate/heptane (1:10 by volume). The product was isolated by filtration(at −8° C.), washed with 1.6 L of cold (−10° C.) ethyl acetate/heptane(1:10 by volume) and air-dried to give 339 g (88% yield) ofβS-2-[Bis(phenylmethyl)amino]benzene-propanol, mp 71.5-73.0° C. Moreproduct can be obtained from the mother liquor if necessary. The otheranalytical characterization was identical to compound prepared asdescribed above.

[0168] Step C:

[0169] A solution of oxalyl chloride (8.4 ml, 0.096 mol) indichloromethane (240 ml) was cooled to −74° C. A solution of DMSO (12.0ml, 0.155 mol) in dichloromethane (50 ml) was then slowly added at arate to maintain the temperature at −74° C. (addition time—1.25 hr). Themixture was stirred for 5 min. followed by addition of a solution of thealcohol (0.074 mol) in 100 ml of dichloromethane (addition time—20 min.,temp. −75° C. to −68° C.). The solution was stirred at −78° C. for 35minutes. Triethylamine (41.2 ml, 0.295 mol) was then added over 10 min.(temp. −78° to −68° C.) upon which the ammonium salt precipitated. Thecold mixture was stirred for 30 min. and then water (225 ml) was added.The dichloromethane layer was separated from the aqueous phase andwashed with water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue was diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate wasconcentrated to give the desired aldehyde product. The aldehyde wascarried on to the next step without purification.

[0170] Temperatures higher than −70° C. have been reported in theliterature for the Swern oxidation. Other Swern modifications andalternatives to the Swern oxidations are also possible.

[0171] Alternatively, the aldehyde was prepared as follows. (200 g,0.604 mol) was dissolved in triethylamine (300 mL, 2.15 mol). Themixture was cooled to 12° C. and a solution of sulfur trioxide/pyridinecomplex (380 g, 2.39 mol) in DMSO (1.6 L) was added at a rate tomaintain the temperature between 8-17° C. (addition time—1.0 h). Thesolution was stirred at ambient temperature under a nitrogen atmospherefor 1.5 hour at which time the reaction was complete by TLC analysis(33% ethyl acetate/hexane, silica gel). The reaction mixture was cooledwith ice water and quenced with 1.6 L of cold water (10-15° C.) over 45minutes. The resultant solution was extracted with ethyl acetate (2.0L), washed with 5% citric acid (2.0 L), and brine (2.2 L), dried overMgSO₄ (280 g) and filtered. The solvent was removed on a rotaryevaporator at 35-40° C. and then dried under vaccuum to give 198.8 g ofas-[Bis-(phenylmethyl)amino]-benzenepropanaldehyde as a pale yellow oil(99.9%). The crude product obtained was pure enough to be used directlyin the next step without purification. The analytical data of thecompound were consistent with the published literature. [α]_(D)25=−92.9°(c 1.87, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) ∂, 2.94 and 3.15 (ABX-System,2H, J_(AB)=13.9 Hz, J_(AX)=7.3 Hz and J_(BX)=6.2 Hz), 3.56 (t, 1H, 7.1Hz), 3.69 and 3.82 (AB-System, 4H, J_(AB)=13.7 Hz), 7.25 (m, 15H) and9.72 (S, 1H); HRMS calcd for (M+1) C₂₃H₂₄NO 330.450, found: 330.1836.Anal. Calcd. for C₂₃H₂₃₀N: C, 83.86; H, 7.04; N, 4.25. Found: C, 83.64;H, 7.42; N, 4.19. HPLC on chiral stationary phase:(S,S) Pirkle-Whelk-O 1column (250×4.6 mm I.D.), mobile phase: hexane/isopropanol (99.5:0.5,v/v), flow-rate: 1.5 ml/min, detection with UV detector at 210 nm.Retention time of the desired S-isomer: 8.75 min., retention time of theR-enanatiomer 10.62 min.

[0172] Step D:

[0173] A solution of αS-[Bis(phenylmethyl)amino] benzene-propanaldehyde(191.7 g, 0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) intetrahydrofuran (1.8 L) was cooled to −30 to −35° C. (colder temperaturesuch as −70° C. also worked well but warmer temperatures are morereadily achieved in large scale operations) in a stainless steel reactorunder a nitrogen atmosphere. A solution of n-butyllithium in hexane (1.6M, 365 mL, 0.58 mol) was then added at a rate that maintained thetemperature below −25° C. After addition the mixture was stirred at −30to −35° C. for 10 minutes. More additions of reagents were carried outin the following manner: (1) additional chloroiodomethane (17 mL) wasadded, followed by n-butyllithium (110 mL) at <−25° C. After additionthe mixture was stirred at −30 to −35° C. for 10 minutes. This wasrepeated once. (2) Additional chloroiodomethane (8.5 mL, 0.11 mol) wasadded, followed by n-butyllithium (55 mL, 0.088 mol) at <−25° C. Afteraddition, the mixture was stirred at −30 to −35° C. for 10 minutes. Thiswas repeated 5 times. (3) Additional chloroiodomethane (8.5 mL, 0.11mol) was added, followed by n-butyllithium (37 mL, 0.059 mol) at <−25°C. After addition, the mixture was stirred at −30 to −35° C. for 10minutes. This was repeated once. The external cooling was stopped andthe mixture warmed to ambient temp. over 4 to 16 hours when TLC (silicagel, 20% ethyl acetate/hexane) indicated that the reaction wascompleted. The reaction mixture was cooled to 10° C. and quenched with1452 g of 16% ammonium chloride solution (prepared by dissolving 232 gof ammonium chloride in 1220 mL of water), keeping the temperature below23° C. The mixture was stirred for 10 minutes and the organic andaqueous layers were separated. The aqueous phase was extracted withethyl acetate (2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material. (The crude product weight was >100%.Due to the relative instability of the product on silica gel, the crudeproduct is usually used directly in the next step without purification).The diastereomeric ratio of the crude mixture was determined by protonNMR: (2S)/(2R): 86:14. The minor and major epoxide diastereomers werecharacterized in this mixture by tlc analysis (silica gel, 10% ethylacetate/hexane), Rf=0.29 & 0.32, respectively. An analytical sample ofeach of the diastereomers was obtained by purification on silica-gelchromatography (3% ethyl acetate/hexane) and characterized as follows:

[0174] N,N,αS-Tris(phenylmethyl)-2S-oxiranemethanamine

[0175]¹H NMR (400 MHz, CDCl₃) a 2.49 and 2.51 (AB-System, 1H,J_(AB)=2.82), 2.76 and 2.77 (AB-System, 1H, J_(AB)=4.03), 2.83 (m, 2H),2.99 & 3.03 (AB-System, 1H, J_(AB)=10.1 Hz), 3.15 (m, 1H), 3.73 & 3.84(AB-System, 4H, J_(AB)=14.00), 7.21 (m, 15H); ¹³C NMR (400 MHz, CDCl₃) ∂139.55, 129.45, 128.42, 128.14, 128.09, 126.84, 125.97, 60.32, 54.23,52.13, 45.99, 33.76; HRMS calcd for C₂₄H₂₆NO (M+1) 344.477, found344.2003.

[0176] N,N,αS-Tris(phenylmethyl)-2R-oxiranemethanamine

[0177]¹H NMR (300 MHz, CDCl₃) ∂ 2.20 (m, 1H), 2.59 (m, 1H), 2.75 (m,2H), 2.97 (m, 1H), 3.14 (m, 1H), 3.85 (AB-System, 4H), 7.25 (m,15H).HPLC on chiral stationary phase: Pirkle-Whelk-O 1 column (250×4.6mm I.D.), mobile phase: hexane/isopropanol (99.5:0.5, v/v), flow-rate:1.5 ml/min, detection with UV detector at 210 nm. Retention time of (8):9.38 min., retention time of enanatiomer of (4): 13.75 min.

[0178] Alternatively, a solution of the crude aldehyde 0.074 mol andchloroiodomethane (7.0 ml, 0.096 mol) in tetrahydrofuran (285 ml) wascooled to −78° C., under a nitrogen atmosphere. A 1.6 M solution ofn-butyllithium in hexane (25 ml, 0.040 mol) was then added at a rate tomaintain the temperature at −75° C. (addition time —15 min.). After thefirst addition, additional chloroiodomethane (1.6 ml, 0.022 mol) wasadded again, followed by n-butyllithium (23 ml, 0.037 mol), keeping thetemperature at −75° C. The mixture was stirred for 15 min. Each of thereagents, chloroiodomethane (0.70 ml, 0.010 mol) and n-butyllithium (5ml, 0.008 mol) were added 4 more times over 45 min. at −75° C. Thecooling bath was then removed and the solution warmed to 22° C. over 1.5hr. The mixture was poured into 300 ml of saturated aq. ammoniumchloride solution. The tetrahydrofuran layer was separated. The aqueousphase was extracted with ethyl acetate (1×300 ml). The combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand concentrated to give a brown oil (27.4 g). The product could be usedin the next step without purification. The desired diastereomer can bepurified by recrystallization at a subsequent step. The product couldalso be purified by chromatography.

[0179] Alternatively, a solution ofαS-[Bis(phenylmethyl)amino]benzene-propanaldehyde (178.84 g, 0.54 mol)and bromochloromethane (46 mL, 0.71 mol) in tetrahydrofuran (1.8 L) wascooled to −30 to −35° C. (colder temperature such as −70° C. also workedwell but warmer temperatures are more readily achieved in large scaleoperations) in a stainless steel reactor under a nitrogen atmosphere. Asolution of n-butyllithium in hexane (1.6 M, 340 mL, 0.54 mol) was thenadded at a rate that maintained the temperature below −25° C. Afteraddition the mixture was stirred at −30 to −35° C. for 10 minutes. Moreadditions of reagents were carried out in the following manner: (1)additional bromochloromethane (14 mL) was added, followed byn-butyllithium (102 mL) at <−25° C. After addition the mixture wasstirred at −30 to −35° C. for 10 minutes. This was repeated once. (2)Additional bromochloromethane (7 mL, 0.11 mol) was added, followed byn-butyllithium (51 mL, 0.082 mol) at <−25° C. After addition the mixturewas stirred at −30 to −35° C. for 10 minutes. This was repeated 5 times.(3) Additional bromochloromethane (7 mL, 0.11 mol) was added, followedby n-butyllithium (51 mL, 0.082 mol) at <−25° C. After addition themixture was stirred at −30 to −35° C. for 10 minutes. This was repeatedonce. The external cooling was stopped and the mixture warmed to ambienttemp. over 4 to 16 hours when TLC (silica gel, 20% ethyl acetate/hexane)indicated that the reaction was completed. The reaction mixture wascooled to 10° C. and quenched with 1452 g of 16% ammonium chloridesolution (prepared by dissolving 232 g of ammonium chloride in 1220 mLof water), keeping the temperature below 23° C. The mixture was stirredfor 10 minutes and the organic and aqueous layers were separated. Theaqueous phase was extracted with ethyl acetate (2×500 mL). The ethylacetate layer was combined with the tetrahydrofuran layer. The combinedsolution was dried over magnesium sulfate (220 g), filtered andconcentrated on a rotary evaporator at 65° C. The brown oil residue wasdried at 70° C. in vacuo (0.8 bar) for 1 h to give 222.8 g of crudematerial.

Example 2

[0180]

[0181] Preparation ofN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenyl]-1-(2-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane

[0182] To a solution of 7.51 g (20.3 mmol) ofN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)]aminein 67 mL of anhydrous tetrahydrofuran was added 2.25 g (22.3 mmol) oftriethylamine. After cooling to 0° C., 4.4 g (20.3 mmol) ofdi-tert-butyldicarbonate was added and stirring continued at roomtemperature for 21 hours. The volatiles were removed in vacuo, ethylacetate added, then washed with 5% citric acid, saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 9.6 g of crude product. Chromatography on silicagel using 30% ethyl acetate/hexane afforded 8.2 g of pureN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenyl]-1-[(2-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane,mass spectum m/e=477 (M+Li).

EXAMPLE 3A

[0183]

[0184] Preparation of phenylmethyl [2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate

[0185] To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylamine(2.0 gm, 5.2 mmol) and triethylamine (723 uL, 5.5 mmol) indichloromethane (20 mL) was added dropwise methanesulfonyl chloride (400uL, 5.2 mmol). The reaction mixture was stirred for 2 hours at roomtemperature, then the dichloromethane solution was concentrated to ca. 5mL and applied to a silica gel column (100 gm). The column was elutedwith chloroform containing 1% ethanol and 1% methanol. The phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate was obtained asa white solid Anal. Calcd for C₂₄H₃₄N₂O₅S: C, 62.31; H, 7.41; N, 6.06.Found: C, 62.17; H, 7.55; N, 5.97.

EXAMPLE 3B

[0186]

[0187] Preparation of phenylmethyl [2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamate

[0188] From the reaction ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylamine(1.47 gm, 3.8 mmol), triethylamine (528 uL, 3.8 mmol) andbenzenesulfonyl chloride (483 uL, 3.8 mmol) one obtains phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-carbamate. Columnchromotography on silica gel eluting with chloroform containing 1%ethanol afforded the pure product. Anal. Calcd for C₂₉H₃₆N₂O₅S: C,66.39; H, 6.92; N, 5.34. Found: C, 66.37; H, 6.93; N, 5.26.

EXAMPLE 4

[0189]

[0190] Preparation of Phenylmethyl [2R-hydroxy-3-[(3-methylbutyl)(n-propanesulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate

[0191] To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl] N-isoamylamine(192 mg, 0.5 mmol) and triethylamine (139 uL, 1.0 mmol) indichloromethane (10 mL) was added dropwise trimethylsilyl chloride (63uL, 0.5 mmol). The reaction was allowed to stir for 1 hour at roomtemperature, cooled to 0° C. with an ice bath and then n-propanesulfonylchloride (56 uL, 0.5 mmol) was added dropwise. The reaction mixture wasstirred for 1.5 hours at room temperature, then diluted with ethylacetate (50 mL) and washed sequentially with 1N HCl, water, saturatedsodium bicarbonate solution, and saturated sodium chloride solution (25mL each). The organic solution was dried over magnesium sulfate,filtered and concentrated to an oil. The oil was stirred with methanol(10 mL) for 16 hours, concentrated and the residue chromatographed onsilica gel (50 gm) eluting with 10% ethyl acetate in hexane (450 mL),then with 1:1 ethyl acetate/hexane. The phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(n-propanesulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate wasrecrystallized from ethyl ether/hexane to afford a white solid Anal.Calcd. for C₂₆H₃₈N₂O₅S: C, 63.64; H, 7.81; N, 5.71. Found: C, 63.09; H,7.74; N, 5.64.

EXAMPLE 5

[0192]

[0193] The procedure described in Example 2 was used to preparephenylmethyl [2S-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate.

[0194] To a solution ofN[3(S)-benzyloxycarbonylamino-2(S)-hydroxy-4-phenylbutyl] N-isoamylamine(192 mg, 0.5 mmol) and triethylamine (139 uL, 0.55 mmol) indichloromethane (8 mL) was added dropwise methanesulfonyl chloride (39uL, 0.55 mmol). The reaction mixture was stirred for 16 hours at roomtemperature, then the dichloromethane solution was applied to a silicagel column (50 gm). The column was eluted with dichloromethanecontaining 2.5% methanol. The phenylmethyl[2S-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate was obtained asa white solid Anal. Calcd. for C₂₄H₃₄N₂O₅S ⋄ 0.2H₂O: C, 61.83; H, 7.44;N, 6.01. Found: C, 61.62; H, 7.40; N, 5.99.

EXAMPLE 6

[0195] Following the procedures of the previous Examples 1-5, theintermediate compounds set forth in Tables 1A and 1B were prepared.TABLE 1A

Entry R³ R⁴ 1 isoamyl p-fluorophenyl 2 isoamyl p-nitrophenyl 3 isoamylo-nitrophenyl 4 isoamyl β-naphthyl 5 isoamyl 2-thienyl 6 isoamyl benzyl7 isobutyl p-fluorophenyl 8 p-fluorobenzyl phenyl 9 4-pyridylmethylphenyl 10 cyclohexylmethyl phenyl 11 allyl phenyl 12 propyl phenyl 13cyclopropylmethyl phenyl 14 methyl phenyl 15 propargyl phenyl 16 isoamylp-chlorophenyl 17 isoamyl p-methoxyphenyl 18 isoamyl m-nitrophenyl 19isoamyl m-trifluoromethylphenyl 20 isoamyl o-methoxycarbonylphenyl 21isoamyl p-acetamidophenyl 22 isobutyl phenyl 23 —CH₂Ph —Ph 24

—Ph 25

—Ph 26

—Ph 27

—Ph 28

—Ph 29 —CH₂CH═CH₂ —Ph 30

—Ph 31

—Ph 32 —CH₂CH₂Ph —Ph 33 —CH₂CH₂CH₂CH₂OH —Ph 34 —CH₂CH₂N(CH₃)₂ —Ph 35

—Ph 36 —CH₃ —Ph 37 —CH₂CH₂CH₂SCH₃ —Ph 38 —CH₂CH₂CH₂S(O)₂CH₃ —Ph 39—CH₂CH₂CH(CH₃)₂

40 —CH₂CH₂CH(CH₃)₂ —CH₂CH₂CH₃ 41 —CH₂CH₂CH(CH₃)₂ —CH₃ 42 —CH₂CH₂CH(CH₃)₂

43 —CH₂CH₂CH(CH₃)₂

44 —CH₂CH₂CH(CH₃)₂

45 —CH₂CH(CH₃)₂

46 —CH₂CH(CH₃)₂

47 —CH₂CH(CH₃)₂

48 —CH₂CH₂CH₃

49 —CH₂CH₂CH₂CH₃

50 —CH₂CH₂CH(CH₃)₂ —CF₃ 51 —CH₂CH(CH₃)₂ —CH₃ 52 —CH₂CH₂CH(CH₃)₂ —CH₂Cl53 —CH₂CH(CH₃)₂

54 —CH₂CH(CH₃)₂

55 —CH₂CH(CH₃)₂ —CH═CH₂ 56 —CH₂—CH)CH₃)(CH₂CH₃)

MASS MEASUREMENT Entry R³ R⁴ MOL FORM CALC FOUND 1

C₂₉H₃₆N₂O₅S 531 (M + Li) 531 2

C₂₉H₃₆N₂O₅S 541 (M + H) 541 3

C₂₉H₃₆N₂O₅S 555.2529 (M + H) 555.2582 4

5

6

C₂₈H₃₃N₂O₅SF 529.2172 (M + H) 521.2976 7

8

C₂₉H₃₆N₂O₅S₂ 563 (M + Li) 563 9

C₂₉H₃₆N₂O₆S₂ 573 (M + H) 573 10

C₂₉H₃₆N₂O₇S₂ 595 (M + Li) 595

[0196] TABLE 1B

Entry R R³ 1

—CH₂Ph 2

—CH₂CH₂CH(CH₃)₂ 3

—CH₂CH(CH₃)₂ 4

—CH₂CH(CH₃)₂ 5

—CH₂CH(CH₃)₂ 6

—CH₂CH(CH₃)₂ 7

—CH₂CH(CH₃)₂ 8

—CH₂CH(CH₃)₂ 9

—CH₂CH₂(CH₃)₂

[0197] TABLE 1C

Mass Determination X R⁸ FORMULA Calc Found H

C₂₇H₃₃N₃O₅S 512.2219(M + H) 521.2267 OCH₃

C₂₈H₃₅N₃O_(O) ₆S 548.2407(M + Li) 548.2434 F

C₂₇H₃₂N₃O₅SF 530(M + H) 530 Cl

C₂₇H₃₂N₃O₅SCl 546(M + H) 546 NO₂

C₂₇H₃₂N₄O₇S 557(M + H) 557 OH

C₂₇H₃₃N₃O₆S 528(M + H) 528 OCH₃

C₂₈H₃₅N₃O₆S 542.2325(M + H) 542.2362 OCH₃

C₂₈H₃₅N₃O₆S 548.2407(M + Li) 548.2393 OCH₃

C₂₈H₃₅N₃O₆S 543(M + H) 543 OCH₃

C₂₉H₃₆O₆N₂S 547.2454(M + Li) 547.2475 OCH₃ tert-Butyl C₂₆H₃₈N₂O₆S513.2611(M + Li) 513.2593 OCH₃

C₂₈H₃₅N₃O₇S 564(M + Li) 564 OCH₃

C₂₈H₃₅N₃O₇S 564(M + Li) 564

[0198] The following Examples 7-9 illustrate preparation of β-amino acidintermediates. These intermediates can be coupled to the intermediatecompounds of Examples 1-6 to produce inhibitor compounds of the presentinvention containing β-amino acids.

EXAMPLE 7

[0199] A. Preparation of 4(4-methoxybenzyl)itaconate

[0200] A 5 L three-necked round bottomed flask equipped with constantpressure addition funnel, reflux condenser, nitrogen inlet, andmechanical stirrer was charged with itaconic anhydride (660.8 g, 5.88mol) and toluene (2300 mL). The solution was warmed to reflux andtreated with 4-methoxybenzyl alcohol (812.4 g, 5.88 mol) dropwise over a2.6 h period. The solution was maintained at reflux for an additional1.5 h and then the contents were poured into three 2 L erlenmeyer flasksto crystallize. The solution was allowed to cool to room temperaturewhereupon the desired mono-ester crystallized. The product was isolatedby filtration on a Buchner funnel and air dried to give 850.2 g, 58% ofmaterial with mp 83-85° C., a second crop, 17% was isolated aftercooling of the filtrate in an ice bath. ¹H NMR (CDCl₃) 300 MHz 7.32 (d,J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 6.49 (s, 1H), 5.85 (s, 1H), 5.12(s, 2H), 3.83 (s, 3H), 3.40 (s, 2H).

[0201] B. Preparation of Methyl 4(4-methoxybenzyl) itaconate

[0202] A 5 L three-necked round bottomed flask equipped with refluxcondenser, nitrogen inlet, constant pressure addition funnel andmechanical stirrer was charged with 4(4-methoxybenzyl) itaconate (453.4g, 1.81 mol) and treated with 1,5-diazabicyclo[4.3.0]non-5-ene (275.6 g,1.81 mol), (DBN), dropwise so that the temperature did not rise above15° C. To this stirring mixture was added a solution of methyl iodide(256.9 g, 1.81 mol) in 250 mL of toluene from the dropping funnel over a45 m period. The solution was allowed to warm to room temperature andstirred for an additional 3.25 h.

[0203] The precipitated DBN hydroiodide was removed by filtration,washed with toluene and the filtrate poured into a separatory funnel.The solution was washed with sat. aq. NaHCO₃ (2×500 mL), 0.2N HCl (1×500mL), and brine (2×500 mL), dried over anhyd. MgSO₄, filtered, and thesolvent removed in vacuo. This gave a clear colorless oil, 450.2 g, 94%whose NMR was consistent with the assigned structure. ¹H NMR (CDCl₃) 300MHz 7.30 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.34 (s, 1H), 5.71(s, 1H), 5.09 (s, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 3.38 (s, 2H). ¹³C NMR(CDCl₃) 170.46, 166.47, 159.51, 133.55, 129.97, 128.45, 127.72, 113.77,66.36, 55.12, 51.94, 37.64.

[0204] C. Preparation of Methyl 4(4-methoxybenzyl) 2(R)-methylsuccinate

[0205] A 500 mL Fisher-Porter bottle was charged with methyl4(4-methoxybenzyl) itaconate (71.1 g, 0.269 mol), rhodium (R,R) DiPAMPcatalyst (204 mg, 0.269 mmol, 0.1 mol %) and degassed methanol (215 mL).The bottle was flushed 5 times with nitrogen and 5 times with hydrogento a final pressure of 40 psig. The hydrogenation commenced immediatelyand after ca. 1 h the uptake began to taper off, after 3 h the hydrogenuptake ceased and the bottle was flushed with nitrogen, opened and thecontents concentrated on a rotary evaporator to give a brown oil thatwas taken up in boiling iso-octane (ca. 200 mL, this was repeatedtwice), filtered through a pad of celite and the filtrate concentratedin vacuo to give 66.6 g, 93% of a clear colorless oil, ¹H NMR (CDCl₃ 300MHz 7.30 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 5.08 (s, 2H), 3.82(s, 3H), 3.67 (s, 3H), 2.95 (ddq, J=5.7, 7.5, 8.7 Hz, 1H), 2.79 (dd,J=8.1, 16.5 Hz, 1H), 2.45 (dd, J=5.7, 16.5 Hz, 1H), 1.23 (d, J=7.5 Hz,3H).

[0206] D. Preparation of Methyl 2(R)-methylsuccinate

[0207] A 3 L three-necked round-bottomed flask equipped with a nitrogeninlet, mechanical stirrer, reflux condenser and constant pressureaddition funnel was charged with methyl 4(4-methoxybenzyl)2(R)-methylsuccinate (432.6 g, 1.65 mol) and toluene (1200 mL). Thestirrer was started and the solution treated with trifluoroacetic acid(600 mL) from the dropping funnel over 0.25 h. The solution turned adeep purple color and the internal temperature rose to 45° C. Afterstirring for 2.25 h the temperature was 27° C. and the solution hadacquired a pink color. The solution was concentrated on a rotaryevaporator. The residue was diluted with water (2200 mL) and sat. aq.NaHCO₃ (1000 ML). Additional NaHCO₃ was added until the acid had beenneutralized. The aqueous phase was extracted with ethyl acetate (2×1000mL) to remove the by-products and the aqueous layer was acidified topH=1.8 with conc. HCl. This solution was extracted with ethyl acetate(4×1000 mL), washed with brine, dried over anhyd. MgSO₄, filtered andconcentrated on a rotary evaporator to give a colorless liquid 251g, >100% that was vacuum distilled through a short path apparatus cut 1:bath temperature 120° C.@>1 mm, bp 25-29° C.; cut 2: bath temperature140° C. @ 0.5 mm, bp 95-108° C., 151 g, [α]_(d) @ 25° C.=+1.38° C.(c=15.475, MeOH), [α]_(d)=+8.48° C. (neat); cut 3: bath temperature 140°C., bp 108° C., 36 g, [α]_(d) @ 25° C.=+1.49° C. (c=15.00, MeOH),[α]_(d)=+8.98° C. (neat). Cuts 2 and 3 were combined to give 189 g, 78%of product, ¹H NMR (CDCl₃) 300 MHz 11.6 (brs, 1H), 3.72 (s, 3H), 2.92(ddq, J=5.7, 6.9, 8.0 Hz, 1H), 2.81 (dd, J=8.0, 16.8 Hz, 1H), 2.47 (dd,J=5.7, 16.8 Hz, 1H), 1.26 (d, J=6.9 Hz, 3H).

[0208] E. Preparation of Methyl Itaconate

[0209] A 50 mL round bottomed flask equipped with reflux condenser,nitrogen inlet and magnetic stir bar was charged with methyl4(4-methoxybenzyl) itaconate (4.00 g, 16 mmol), 12 mL of touluene and 6mL of trifluoroacetic acid. The solution was kept at room temperaturefor 18 hours and then the volatiles were removed in vacuo. The residuewas taken up in ethyl acetate and extracted three times with saturatedaqueous sodium bicarbonate solution. The combined aqueous extract wasacidified to pH=1 with aqueous potassium bisulfate and then extractedthree times with ethyl acetate. The combined ethyl acetate solution waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The residue wasthen vacuum distilled to give 1.23 g, 75% of pure product, bp 85-87 @0.1 mm. ¹H NMR (CDCl₃) 300 MHz 6.34 (s, 1H), 5.73 (s, 2H), 3.76 (s, 3H),3.38 (s, 2H). ¹³C NMR (CDCl₃) 177.03, 166.65, 129.220, 132.99, 52.27,37.46.

[0210] F. Curtius Rearrangement of Methyl 2(R)-methylsuccinate:Preparation of Methyl N-Moz-α-methyl β-alanine.

[0211] A 5 L four necked round bottomed flask equipped with a nitrogeninlet, reflux condenser, mechanical stirrer, constant pressure additionfunnel, and thermometer adapter was charged with methyl2(R)-methylsuccinate (184.1 g, 1.26 mol), triethylamine (165.6 g, 218mL, 1.64 mol, 1.3 equivalents), and toluene (1063 mL). The solution waswarmed to 85° C. and then treated dropwise with a solution ofdiphenylphosphoryl azide (346.8 g, 1.26 mol) over a period of 1.2 h. Thesolution was maintained at that temperature for an additional 1.0 h andthen the mixture was treated with 4-methoxybenzyl alcohol (174.1 g, 1.26mol) over a 0.33 h period from the dropping funnel. The solution wasstirred at 88° C. for an additional 2.25 h and then cooled to roomtemperature. The contents of the flask were poured into a separatoryfunnel and washed with sat. aq. NaHCO₃ (2×500 mL), 0.2N HCl (2×500 mL),brine (1×500 mL), dried over anhyd. MgSO₄, filtered, and concentrated invacuo to give 302.3 g, 85% of the desired product as a slightly brownoil. ¹H NMR (CDCl₃) 300 MHz 7.32 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz,2H), 5.2 (brm, 1H), 5.05 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H), 3.35 (m,2H), 2.70 (m, 2H), 1.20 (d, J=7.2 Hz, 3H).

[0212] G. Hydrolysis of Methyl N-Moz-α-methyl β-alanine: Preparation ofα-methyl β-alanine Hydrochloride

[0213] A 5 L three-necked round bottomed flask equipped with a refluxcondenser, nitrogen inlet and mechanical stirrer was charged with methylN-Moz-α-methyl β-alanine (218.6 g, 0.78 mol), glacial acetic acid (975mL) and 12N hydrochloric acid (1960 mL). The solution was then heated toreflux for 3 h. After the solution had cooled to room temperature (ca. 1h) the aqueous phase was decanted from organic residue (polymer) and theaqueous phase concentrated on a rotary evaporator. Upon addition ofacetone to the concentrated residue a slightly yellow solid formed thatwas slurried with acetone and the white solid was isolated by filtrationon a Buchner funnel. The last traces of acetone were removed byevacuation to give 97.7 g, 90% of pure product, mp 128.5-130.5° C.[α]_(d)@ 25° C.=9.0° C. (c=2.535, Methanol). ¹H NMR (D₂O) 300 MHz 3.29(dd, J=8.6, 13.0 Hz, 1H), 3.16 (dd, J=5.0, 13.0 m Hz, 1H), 2.94 (ddq,J=7.2, 5.0, 8.6 Hz, 1H), 1.30 (d, J=7.2 Hz, 3H); ¹³C NMR (D₂O) 180.84,44.56, 40.27, 17.49.

[0214] H. Preparation of N-Boc α-Methyl β-Alanine

[0215] A solution of α-methyl b-alanine hydrochloride (97.7 g, 0.70 mol)in water (1050 mL) and dioxane (1050 mL) the pH was adjusted to 8.9 with2.9N NaOH solution. This stirring solution was then treated withdi-tert-butyl pyrocarbonate (183.3 g, 0.84 mol, 1.2 equivalents) all atonce. The pH of the solution was maintained between 8.7 and 9.0 by theperiodic addition of 2.5N NaOH solution. After 2.5 h the pH hadstabilized and the reaction was judged to be complete. The solution wasconcentrated on a rotary evaporator (the temperature was maintained at<40° C.). The excess di-tert-butyl pyrocarbonate was removed byextraction with dichloromethane and then the aqueous solution wasacidified with cold 1N HCl and immediately extracted with ethyl acetate(4×1000 ML). The combined ethyl acetate extract was washed with brine,dried over anhyd. MgSO₄, filtered and concentrated on a rotaryevaporator to give a thick oil 127.3 g, 90% crude yield that was stirredwith n-hexane whereupon crystals of pure product formed, 95.65 g, 67%,mp 76-78° C., [α]_(d)@ 25° C.=−11.8° C. (c=2.4, EtOH). A second crop wasobtained by concentration of the filtrate and dilution with hexane, 15.4g, for a combined yield of 111.05 g, 78%. ¹H NMR (acetone D₆) 300 MHz11.7 (brs, 1H), 6.05 (brs 1H), 3.35 (m, 1H), 3.22 (m, 1H), 2.50 (m, 1H),1.45 (s, 9H), 1.19 (d, J=7.3 Hz, 3H); ¹³C NMR (acetone D₆) 177.01,79.28, 44.44, 40.92, 29.08, 15.50. Elemental analysis calc'd. forC₉H₁₇NO₄: C, 53.19, H, 8.42; N, 6.89. Found: C, 53.36; H, 8.46; N, 6.99.

[0216] I. Preparation of N-4-Methoxybenzyloxycarbonyl α-Methyl β-Alanine

[0217] A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alaninemethyl ester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol wastreated with lithium hydroxide (1.3 equivalents) at room temperature fora period of 2 h. The solution was concentrated in vacuo and the residuetaken up in a mixture of water and ether and the phases separated andthe organic phase discarded. The aqueous phase was acidified withaqueous potassium hydrogen sulfate to pH=1.5 and then extracted threetimes with ether. The combined ethereal phase was washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give 2.60 g, 97% ofN-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which waspurified by recrystallization from a mixture of ethyl acetate and hexaneto give 2.44 g, 91% of pure product, mp 96-97° C., MH+=268. ¹H NMR(D₆-acetone/300 MHz) 1.16 (3H, d, J=7.2 Hz), 2.70 (1H, m), 3.31 (2H, m),3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7Hz).

EXAMPLE 8

[0218] Following generally the procedure of Example 7, the β-amino acidsset forth in Table 1 were prepared. TABLE 2

Entry R¹ R^(1′) R^(1″) 1 —CH₃ H H 2 —CH(CH₃)₂ H H 3 —C(CH₃)₃ H H 4 H H H5 H —CH₃ H 6 H —CH₃ —CH₃ 7 H H —CO2CH₃ 8 H H —CONH₂ 9 —CH₂CH₃ H H 10—CH₂CH(CH₃)₂ H H 11 —CH₂C₆H₅ H H 12

H H 13

H H 14 —CH₂COOH H H 15 H —CH(CH₃)₂ H 16 H —CH₂CH(CH₃)₂ H 17 H

H 18 H

H 19 H

H 20 H

H 21 H —(CH₂)₃CH(C₆H₅)₂ H

EXAMPLE 9

[0219] Utilizing generally the procedure set forth in Example 7, thefollowing β-amino acid compounds were prepared.

EXAMPLE 10A

[0220]

[0221] Preparation of 4-Pyridinecarboxamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl) amino]-1S—(phenylmethyl)propyl]

[0222] To a solution of 231 mg (0.57 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 3 mL of methylene chloride at O C, was added 288 mg (2.85 mmol) oftriethylamine and then 112 mg (0.63 mmol) of isonicotinoyl chloridehydrochloride. After 19 hours at room temperature, the solvent wasremoved, ethyl acetate added, then washed with saturated sodiumbicarbonate, brine, dried with magnesium sulfate, filtered andconcentrated to afford 290 mg of crude product. This was chromatographedon silica gel using 3-5% isopropanol/methylene chloride as eluent toafford 190 mg of the desired compound; mass spectrum calc. forC₂₇H₃₄N₃O₅S (M+H) 512.2219; found 512.2280.

EXAMPLE 10B

[0223]

[0224] Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2,6-dimethyl

[0225] To a solution of 83 mg (0.55 mmol) of 2,6-dimethylbenzoic acidand 125 mg (0.82 mmol) of N-hydroxybenzotriazole in 3 mL of anhydrousDMF at O C was added 117 mg (0.61 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After 2hours at O C, 203 mg (0.50 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 22 hours at room temperature, the solvent was removedin vacuo, ethyl acetate added, then washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 300 mg of crude product. Chromatography on silicagel using 20-50% ethyl acetate/hexane afforded 37 mg of the desiredproduct; mass spectrum calcd for C₃₀H₃₈N₂O₅S (M+H) 539.2580; found539.2632.

EXAMPLE 1C

[0226]

[0227] Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl.

[0228] Part A. Preparation of 4-Nitro-2-methylbenzoic Acid.

[0229] A mixture of 11.0 g (3.8 mmol) of 2-iodo-nitrotoluene, 2.1 g(15.2 mmol) potassium carbonate and 27 mg (0.038 mmol) of palladium(II)dichloride bis(triphenylphosphine) in a mixture of 5 mL of water and 10mL of N,N-dimethylformamide. This was placed in a Fisher/Porter bottleunder 15 psig of carbon monoxideand heated at 70 C for 16 hours. Thesolution became homogeneous when heated. The reaction was cooled,diethyl ether and water was added, the organic layer separated anddiscarded. The aqueous layer was acidified with 1N hydrohloric acid,extracted with ethyl acetate, washed with water, brine, dried overmagnesium sulfate, filtered and concentrated to yield 0.5 g of crudematerial. This dissolved in ethyl acetate, hexane added and theresulting brown solid discarded. The filtrate was concentrated, and thenrecrystallized fom diethyl ether/hexane to afford 215 mg of4-nitro-2-methylbenzoic acid, m/e=182 (M+H).

[0230] Part B. Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitro.

[0231] To a solution of 181 mg (1.0 mmol) of 4-nitro-2-methylbenzoicacid and 230 mg (1.5 mmol) N-hydroxybenzotriazole in 3 mL of anhydrousN,N-dimethylformamide at 0 C, was added 211 mg (1.1 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Afterstirring at 0 C for 1 hour, 406 mg (1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 17 hours at room temperature, the solvent was removedunder reduced pressure, ethyl acetate added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried with magnesium sulfate,filtered and concentrated to yield 0.55 g of crude product. This waschromatographed on silica gel using 20-50% ethyl acetate/hexane aseluent to afford 0.49 g of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitro,m/e=570 (M+H).

[0232] Part C. Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-amino.

[0233] A solution of 400 mg (0.70 mmol) of benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitrofrom part B in 20 mL of methanol was hydrogenated over 0.2 g of 10%palladium on carbon catalyst under 50 psig of hydrogen for 2.5 hours.The catalyst was removed by filtration and the solution concentrated toafford 370 mg of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-amino,m/e=540 (M+H).

[0234] Part D. Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-dimethylamino.

[0235] A solution of 0.17 g (0.31 mmol) of benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-aminofrom part C in 5 mL of methanol and 0.20 mL of 37% aqueous formaldehydewas hydrogenated over 90 mg of 10% palladium on carbon under 15 psig ofhydrogen for 16 hours. The catalyst was removed by filtration, thesolvents removed under reduced pressure to afford 0.16 g of crudematerial. Chromatography on silica gel using 50% ethyl acetate as eluentafforded 0.12 g of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-dimethylamino,m/e=568 (M+H)

EXAMPLE 10D

[0236]

[0237] Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl.

[0238] To a solution of 500 mg (1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 2 mL of methylene chloride and 2 mL of N,N-dimethylformamide, wasadded 0.42 mL of triethylamine, followed by 0.12 mL of ortho-toluoylchloride. After 17 hours, the solvent was removed under reducedpressure, the residue dissolved in ethyl acetate, was with 5% citricacid, saturated sodium bicarbonate and brine, dried over anhydrousmagnesium sulfate, filtered and concentrated to afford 490 mg of crudematerial. This was chromatographed over 100 g of silica gel using 20-50%ethyl acetate/hexane as eluent to afford 232 mg of the desired product,m/e=511 (M+H).

EXAMPLE 11A

[0239]

[0240] Preparation ofN1-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide

[0241] Part A:

[0242] A solution of phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamateprepared as in Example 3 (100 mg) in methanol (10 mL) was hydrogenatedover 10% palladium on carbon for 2 hours, filtered through diatomaceousearth and concentrated to give the product as an oil.

[0243] Part B:

[0244] A solution of N-CBZ-L-asparagine (61 mg, 0.23 mmol) andN-hydroxybenzotriazole (33 mg, 0.22 mmol) in DMF (2 mL) was cooled to 0°C. with an ice bath and then EDC (42 mg, 0.22 mmol) was added. Thesolution was stirred for 30 minutes at 0° C. and then the product ofPart A (69 mg, 0.21 mmol) in DMF (2 mL) was added. After 30 minutes at0° C. the reaction was allowed to warm to room temperature and stir for16 hours. The reaction mixture was then poured into a 50% saturatedaqueous solution of sodium bicarbonate (100 mL) and the resulting whiteprecipitate collected by suction filtration, washed with water and driedin vacuo. The phenylmethyl [3-amino-1S-[[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamatewas obtained as a white solid Anal. Calcd. for C₂₈H₄₀N₄O₇S. 0.5H₂O: C,57.42; H, 7.06; N, 9.57. Found: C, 57.72; H, 7.21; N, 9.24.

[0245] Part C:

[0246] A solution of phenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamate(135 mg, 0.23) in methanol (15 mL) was hydrogenated over 10% palladiumon carbon for 6 hours, filtered through diatomaceous earth andconcentrated to give the product as an oil.

[0247] Part D:

[0248] To a solution of the product from Part C (101 mg, 0.23 mmol) inDMF (5 mL) was added 2-quinoline carboxylic acid N-hydroxysuccinimideester (67 mg, 0.25 mmol). The reaction was stirred at room temperaturefor 16 hours, then poured into a 50% saturated solution of sodiumbicarbonate (60 mL). The resulting solid was collected by suctionfiltration washed with water and dried in vacuo. TheN1-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)-amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)-amino]butanediamidewas obtained as a white solid Anal. Calcd. for C₃₀H₃₉N₅O₆S. 0.1H₂O: C,58.52; H, 6.71; N, 11.37. Found: C, 58.34; H, 6.35; N, 11.13.

EXAMPLE 11B

[0249]

[0250] Preparation of N1-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide.

[0251] Part A:

[0252] The CBZ protected compound phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate(200 mg, 0.38 mmol) was deprotected by hydrogenation over 10% palladiumon carbon and the resulting product obtained as an oil.

[0253] Part B:

[0254] The free amine from Part A was coupled with N-CBZ-L-asparagine(109 mg, 0.41 mmol) in the presence of N-hydroxybenzotriazole (63 mg,0.41 mmol) and EDC (77 mg, 0.40 mmol) to give phenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamateas a white solid Anal. Calcd. for C₃₃H₄₂N₄O₇S: C, 62.05; H, 6.63; N,8.77. Found: C, 61.86; H, 6.60; N, 8.64.

[0255] Part C:

[0256] The product of Part B (110 mg, 0.17) was deprotected byhydrogenation over 10% palladium on carbon to give the product as anoil.

[0257] Part D:

[0258] The resulting free amine was coupled with 2-quinoline carboxylicacid N-hydroxysuccinimide ester (45 mg, 0.17 mmol) to giveN1-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamideas a white solid Anal. Calcd for C₃₅H₄₁N₅O₆S: C, 63.71; H, 6.26; N,10.61. Found: C, 63.59; H, 6.42; N, 10.42.

EXAMPLE 12A

[0259]

[0260] Preparation of2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3.3-dimethylbutanamide

[0261] Part A:

[0262] To a solution of N-CBZ-L-tert-leucine (100 mg, 0.38 mmol) andN-hydroxybenzotriazole (52 mg, 0.34 mmol) in DMF (3 mL) was added EDC(65 mg, 0.34 mmol). The solution was stirred for 60 minutes at roomtemperature and then the product of Example 10, Part A (105 mg, 0.32mmol) in DMF (2 mL) was added. The reaction was stirred for 16 hours atroom temperature, then poured into a 50% saturated solution of sodiumbicarbonate (50 mL). The aqueous mixture was extracted twice with ethylacetate (25 mL). The combined ethyl acetate layers were washed withwater (25 mL) and dried over magnesium sulfate. Filtration andconcentration produced an oil which was chromatographed on silica gel(50 gm) eluting with 2.5% methanol in dichloromethane. The phenylmethyl[1S-[[[2R-hydroxy-3-[(3-methylbutyl)-(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]-carbonyl]-2,2-dimethylpropyl]carbamatewas obtained as a gummy solid

[0263] Anal. Calcd. for C₃₀H₄₅N₃O₆S ⋄ 2.2H₂O: C, 58.55; H, 8.09; N,6.83. Found: C, 58.38; H, 7.77; N, 7.10.

[0264] Part B:

[0265] A solution of phenylmethyl [1S-[[[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamate(100 mg, 0.17 mmol) in methanol (10 mL) was hydrogenated over 10%palladium on carbon for 2 hours. The reaction was filtered throughdiatomaceous earth and concentrated to an oil.

[0266] Part C:

[0267] N,N-dimethylglycine (20 mg, 0.19 mmol), N-hydroxybenzotriazole(28 mg, 0.18 mmol) and EDC (35 mg, 0.18 mmol) were stirred in DMF (4 mL)at room temperature for 40 minutes. The product from Part B in DMF (4mL) was added and the reaction mixture stirred for 16 hours, then pouredinto a 50% saturated sodium bicarbonate solution (50 mL). The aqueousmixture was extracted three times with dichloromethane (30 mL) which inturn were washed with water (30 mL) and dried over magnesium sulfate.Filtration and concentration afforded an oil. The oil waschromatographed on silica gel (50 gm) eluting initially with 2.5%methanol in dichloromethane (400 mL) and then with 5% methanol indichloromethane. The2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamidewas obtained as a white solid Anal. Calcd. for C₂₆H₄₆N₄O₅S ⋄ 0.5 CH₂Cl₂:C, 56.04; H, 8.34; N, 9.87. Found: C, 56.06; H, 8.36; N, 9.70.

EXAMPLE 12B

[0268]

[0269] Preparation of2S-[[(dimethylamino)acetyl]amino]-N—[2R-hydroxy-3-[(3-methyl-butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide

[0270] Part A:

[0271] To a solution of N-CBZ-L-tert-leucine (450 mg, 1.7 mmol) andN-hydroxybenzotriazole (260 mg, 1.7 mmol) in DMF (10 mL) was added EDC(307 mg, 1.6 mmol). The solution was stirred for 60 minutes at roomtemperature and then the product of Example 11, Part A (585 mg, 1.5mmol) in DMF (2 mL) was added. The reaction was stirred for 16 hours atroom temperature, then poured into a 50% saturated solution of sodiumbicarbonate (200 mL). The aqueous mixture was extracted thrice withethyl acetate (50 mL). The combined ethyl acetate layers were washedwith water (50 mL) and saturated NaCl solution (50 mL), then dried overmagnesium sulfate. Filtration and concentration produced an oil whichwas chromatographed on silica gel (50 gm) eluting with 20% ethyl acetatein hexane. The phenylmethyl [1S-[[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamatewas obtained as a solid Anal. Calcd for C₃₅H₄₇N₃O₆-S: C, 65.91; H, 7.43;N, 6.59. Found: C, 65.42; H, 7.24; N, 6.55.

[0272] Part B:

[0273] A solution of phenylmethyl [1S-[[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)-amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamate(200 mg, 0.31 mmol) in methanol (15 mL) was hydrogenated over 10%palladium on carbon for 2 hours. The reaction was filtered throughdiatomaceous earth and concentrated to an oil.

[0274] Part C:

[0275] The resulting free amine from part B (150 mg, 0.3 mmol) wascombined with diisopropylethylamine (114 uL, 0.33 mmol) indichloromethane (5 mL). To this was added bromoacetyl chloride (27 uL,0.33 mmol) dropwise. The reaction was stirred for 30 minutes at roomtemperature, then diluted with dichloromethane (30 mL) and extractedwith 1 N HCl, water, and then saturated NaCl solution (25 mL each). Theorganic solution was dried over MgSO₄ and concentrated to a solid. The2S-[[bromoacetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamidewas sufficiently pure for use in the next step. This material can alsobe prepared by substituing bromoacetic anhydride for bromoacetylchloride, or one can use chloroacetyl chloride or chloracetic anhydride.

[0276] Part D:

[0277] The product from part C was dissolved in dichloromethane (5 mL)and diisopropylethylamine (114 uL, 0.66 mmol) and dimethylaminehydrochloride (53 mg, 0.66 mmol) were added. The reaction was stirredfor 18 hours then concentrated under a stream of nitrogen to about 1 mL.The residue was chromatographed on silica gel (50 gm) using 2% methanolin dichloromethane. The2S-[[(dimethylamino)-acetyl]amino]-N-[2R-hydroxy-3-[(3methylbutyl)-(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide was obtained as a solid. Anal. Calcd forC₃₁H₄₈N₄O₅S: C, 63.24; H, 8.22; N, 9.52. Found: C, 63.03; H, 8.01; N,9.40.

EXAMPLE 12C

[0278]

[0279] Preparation of2S-[[(methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3.3-dimethylbutaneamide

[0280]2S-[[bromoacetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide(103 mg, 0.16 mmol) and 40% aqueous methylamine (42 uL, 0.49 mmol) werecombined in ethanol (2 mL) and stirred at room temperature for 24 hours.The reaction mixture was concentrated to dryness and triturated withether. The solid material was removed by filtration and the filtrateconcentrated to an oil. The oil was chromatographed on silica (50 gm)using 4% methanol in dichloromethane. The2S-[[(methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamidewas obtained as a solid. Anal. Calcd for C₃₀H₄₆N₄O₅S: C, 62.69; H, 8.07;N, 9.75. Found: C, 62.38; H, 8.14; N, 9.60.

EXAMPLE 12D

[0281]

[0282] Preparation of Pentanamide,2S-[[(Dimethylamino))acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]3S-methyl-

[0283] Part A:

[0284] To a solution the amine product of Example 11, Part A; (2.79 g,7.1 mmol) in 27 mL of dioxane was added (2.3 g, 7.1 mmol) ofN-t-butylcarbonyl-L-isoleucine-N-hydroxysuccinamide ester, and thereaction was stirred under nitrogen atmosphere for 16 hours. Thecontents of the reaction were concentrated in vacuo, and the residuedissolved in ethyl acetate, washed with potassium hydrogen sulfate (5%aqueous), saturated sodium bicarbonate, and saturated sodium chloride.The organic layer was dried over magnesium sulfate, filtered andconcentrated to yield 4.3 grams of crude material which waschromatographed using 3:1 ethyl acetate:hexane to obtain 3.05 g, 72%yield of Pentanamide,2S-[[(1,1-dimethylethoxy)carbonyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-.

[0285] Part B

[0286] (3.05 g, 5.0 mmol) of the product from Part A; was dissolved in20 mL of 4N HCl in dioxane and stirred under nitrogen atmosphere for 1.5hours. The contents were concentrated in vacuo, and chased with diethylether. The crude hydrochloride salt was pumped on at 1 mm Hg until dryto yield 2.54 g of product as its hydrochloride salt.

[0287] Part C:

[0288] (2.54 g, 5.0 mmol) of amine hydrochloride was dissolved in 50 mLof tetrahydrofuran and to this was added (1.01 g, 10 mmol) of4-methyl-morpholine, at which time a precipitate forms. To thissuspension was added chloroacetic anhydride (0.865 g, 5.0 mmol) andstirred for 40 minutes. The contents were concentrated in vacuo, and theresidue partitioned in ethyl acetate (200 mL) and 5% KHSO₄. The organiclayer was washed with saturated sodium bicarbonate, and saturated sodiumchloride, dried over magnesium sulfate, filtered and concentrated toyield the crude product. Purification by silica gel chromatography usingan eluant of 1:1 ethyl acetate; hexanes yielded 1.89 grams of purechloroacetamide.

[0289] Part D:

[0290] To a solution of chloroacetamide (1.89 g, 3.2 mmol) from Part C,in 25 mL of tetrahydrofuran was added 4.0 mL of 50% aqueousdimethylamine and the solution was stirred for 1 hour. The solution wasconcentrated in vacuo and the residue was dissolved in ethyl acetate andwashed with water. The organic layer was dried over magnesium sulfate,filtered and concentrated to yield the crude product which was purifiedby crystallization from ethyl acetate and isooctane to yield 1.80 g,(88% yield), mp. =121-122 C, HRes. MS. calc. 589.3424, found 589.3405.

EXAMPLE 12E

[0291]

[0292] Preparation of Pentanamide.2S-[[(Methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-

[0293] To a solution of the chloroacetamide of Example 12D, Part C,(2.36 g, 4.0 mmol) in tetrahydrofuran (25 mL) was added 3 mL of aqueousmethylamine 40 wt %, and the reaction stirred for 1 hour. The contentswere concentrated and the residue was partitioned between ethyl acetate(100 mL) and water (100 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated to yield the crude product, which waspurified by recrystallization from ethyl acetate heptane; (M+H)575,HRes.found 575.3267.

Example 12F

[0294]

[0295] Preparation of Pentanamide.2S-[[(Dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-

[0296] Part A:

[0297] To a solution of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenylsulfonyl)amino]1-S-propylamine(1.70 g, 4.18 mmol) in 40 mL of dichloromethane was addedN-carbobenzyloxy-L-isoleucine-N-hydroxysuccinamide ester (1.51 g, 4.18mmol) and the solution stirred under nitrogen atmosphere for 16 hours.The contents were concentrated in vacuo and the residue was redissolvedin ethyl acetate. The ethyl acetate solution was washed with an aqueoussolution of 5% KHSO₄, saturated sodium bicarbonate, and saturated sodiumchloride, dried over magnesium sulfate, filtered, and concentrated toyield 2.47 g of crude product. The product was purified by silica gelchromatography using 1 2:1 hexane:ethyl acetate eluant to yield 2.3 g.(84% yield) of Pentanamide,2-[(carbobenzyloxy)amino]-N-[2-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1-(phenylmethyl)propyl]-3-methyl-,[4-(R*,S*,S*,)].

[0298] Part B:

[0299] (1.18 g, 1.8 mmol) of the product from Part A was dissolved in 50mL of methanol, and to this was added 250 mg of 10% Palladium on Carbonwhile under a stream of nitrogen. The suspension was hydrogenated using50 psig of hydrogen for 20 hours. The contents were purged with nitrogenand filtered through celite, and concentrated in vacuo to yield 935 mgof Pentanamide,2S-(amino)-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1-S-(phenylmethyl)propyl]-3S-methyl-,which was used without further purification.

[0300] Part C:

[0301] (0.935 g, 1.8 mmol) of the amine from Part B was dissolved in 15mL of dioxane and to this was added (190 mg, 1.85 mmol) of4-methylmorpholine folowed by (0.315 g, 1.8 mmol) of chloroaceticanhydride. The reaction mixture was stirred under nitrogen atmospherefor 3 hours, concentrated in vacuo, and redissolved in ethyl acetate.The ethyl acetate solution was washed with 50 mL of 5% agueous KHSO4,saturated NaHCO₃, and saturated NaCl solution, dried over MgSO₄,filtered and concentrated to yield 613 mg, (68% yield) of Pentanamide,2S-[(chloroacetyl)amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-,after purification by silica gel chromatography using 1:1 hexane:ethylacetate.

[0302] Part D:

[0303] To a solution of the chloroacetamide from Part C; (673 mg, 1.10mmol) in 20 mL of tetrahydrofuran was added 5 mL of 50 wt % aqueousdimethylamine and the solution was stirred for 1 hour. The reaction wasconcentrated and the residue was redissolved in 50 mL of ethyl acetateand washed with 25 mL of water. The ethyl acetate layer was dried overmagnesium sulfate, filtered and concentrated to yield a crude solidwhich was purified by silica gel column chromatography using an eluantof 97:3 dichloromethane:methanol to proivde 400 mg of Pentanamide,2S-[[Dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-.

EXAMPLE 13A

[0304]

[0305] Preparation of Carbamic acid.[2R-hydroxy-3-[[(4-dimethylaminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester

[0306] To a solution of 100 mg (0.19 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester in 1 mL of pyridine was added 53 μL of triethylamineand 120 μL (p.95 mmol) of 40% aqueous dimethylamine. After heating for24 hours at 100 C, the solution was cooled, ethyl acetate added, thenwashed with 5% citric acid, saturated sodium bicarbonate, dried overmagnesium sulfate, filtered and concentrated. The resulting solid wasrecrystallized from ethyl acetate/hexane to afford 10 mg of the desiredproduct; mass spectrum m/e=540 (M+H).

EXAMPLE 13B

[0307]

[0308] Preparation of Carbamic Acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester

[0309] Part A:

[0310] A solution ofN-benzyloxycarbonyl-3S-amino-1,2-S-epoxy-4-phenylbutane (50 g, 0.168mol) and isobutylamine (246 g, 3.24 mol) in 650 mL of isopropyl alcoholwas refluxed for 1.25 hours. The solution was cooled to roomtemperature, concentrated in vacuo and then poured into 1 L of stirringhexane whereupon the product crystallized from solution, was collectedand air dried to give 57.6 g ofN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine, mp108-109.5 C, mass spectrum m/e=371 (M+H).

[0311] Part B:

[0312] The amine from part A (1.11 g, 3.0 mmol) and triethylamine (324mg, 3.20 mmol) in 20 mL of methylene chloride was treated with 715 mg(3.46 mmol) of 4-methoxybenzenesulfonyl chloride. The solution wasstirred at room temperature for 6 hours, concentrated, dissolved inethyl acetate, then washed with 1N potassium hydrogen sulfate, saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford a clear oil. This was recrystallized from diethylether to afford 1.27 g of carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester, mp 97-101 C, mass spectrum m/e=541 (M+H).

[0313] Part C:

[0314] A solution of 930 mg (3.20 mmol) of the product of part B in 30mL of methanol was hydrogenated in the presence of 70 mg of a 10%palladium on carbon catalyst under 40 psig for 17 hours, the catalystwas removed by filtration, and the solution concentrated to afford 704mg of[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine,mass spectrum m/e=407 (M+H), which was used directly in the next stepwithout purification.

[0315] Part D:

[0316] To a solution of 2.5 g (22.9 mmol) of 3-pyridylcarbinol in 100 mLof anhydrous acetonitrile was added 8.8 g (34.4 mmol) ofN,N′-disuccinimidyl carbonate and 5.55 mL (68.7 mmol) of pyridine. Thesolution was stirred for 1 hour and then concentrated in vacuo. Theresidue was dissolved in ethyl acetate, then washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 5.3 g of N-Hydroxysuccinimide-3-pyridylmethylcarbonate, mass spectrum m/e=251 (M+H), which was used directly in thenext step without purification.

[0317] Part E:

[0318] To a solution of the amine from part C (2.87 g, 7.0 mmol) and1.38 mL of triethylamine in 24 mL of anhydrous methylene chloride wasadded a solution of 1.65 g (6.6 mmol) of N-hydroxysuccinimide-3-pyridylcarbonate from part D in 24 mL of methylene chloride. The solution wasstirred for 1 hour, 100 mL of methylene chloride added, then washed withsaturated sodium bicarbonate, brine, dried over sodium sulfate, filteredand concentrated to afford 3.69 g of crude product.

[0319] Chromatography on silica gel using 2% methanol/methylene chlorideto afford 3.27 g of carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, mass spectrum m/e=548 (M+Li).

EXAMPLE 13C

[0320]

[0321] Preparation of Carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-pyridylmethylester

[0322] Part A:

[0323] A solution ofN-benzyloxycarbonyl-3S-amino-1,2-S-epoxy-4-phenylbutane (50 g, 0.168mol) and isobutylamine (246 g, 3.24 mol) in 650 mL of isopropyl alcoholwas refluxed for 1.25 hours. The solution was cooled to roomtemperature, concentrated in vacuo and then poured into 1 L of stirringhexane whereupon the product crystallized from solution, was collectedand air dried to give 57.6 g ofN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine, mp108-109.5 C, mass spectrum m/e=371(M+H).

[0324] Part B:

[0325] 30. The amine from part A (0.94 g, 2.5 mmol) and triethylamine(288 mg, 2.85 mmol) in 20 mL of methylene chloride was treated with 461mg (2.61 mmol) of benzenesulfonyl chloride. The solution was stirred atroom temperature for 16 hours, concentrated, dissolved in ethyl acetate,then washed with 1N potassium hydrogen sulfate, saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford a clear oil. This was recrystallized from diethylether and hexane to afford 0.73 g of carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester, mp 95-99 C, mass spectrum m/e=511 (M+H).

[0326] Part C:

[0327] A solution of 500 mg of carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester in 20 mL of methanol was hydrogenated in the presenceof 250 mg of a 10% palladium on carbon catalyst under 40 psig for 3hours, the catalyst was removed by filtration, and the solutionconcentrated to afford 352 mg of[2R-hydroxy-3-[(phenylsulfonyl])2-methylpropyl)amino]-1S-(phenylmethyl)propylamine,mass spectrum m/e=377 (M+H), which was used directly in the next stepwithout purification.

[0328] Part D:

[0329] To a solution of 1.24 mmol of 5-norbornene-2,3-dicarboximidocarbonochloridate (Henklein, P., et. al., Synthesis 1987, 166-167) in 1mL of anhydrous methylene chloride, was added a solution of 43 μL (2.44mmol) of 3-pyridylcarbinol and 129 μL (1.6 mmol) of pyridine in 1 mL ofmethylene chloride at 0° C. under a nitrogen atmosphere. After 4 hoursat room temperature, 150 mg (0.4 mmol) of[2R-hydroxy-3-[(phenylsulfonyl])2-methylpropyl)amino]-1S-(phenylmethyl)propylaminefrom Part C above was added and 100 μL of pyridine. After stirring for15 hours at room temperature, ethyl acetate was added, then washed with1N hydrochloric acid, saturated sodium bicarbonate, brine, dried overmagnesium sulfate, filtered and concentrated to afford 175 mg of crudeproduct. Chromatography over silica gel using 1% methanol/methylenechloride tp afford 69 mg of pure carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, mass spectrum m/e=512.2267 (M+H); calcd forC₂₇H₃₃N₃O₅S, 512.2219.

EXAMPLE 13D

[0330]

[0331] Preparation of Carbamic acid,[2R-hydroxy-3-r[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, N-oxide

[0332] To a solution of 211 mg (0.39 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester in 5 mL of methylene chloride at O C was added 500mg of 50% 3-chloroperbenzoic acid. After stirring at room temperaturefor 1 hour, ethyl acetate was added, the solution washed with saturatedsodium bicarbonate, 0.2N ammonium hydroxide solution and brine, driedover magnesium sulfate, filtered and concentrated to afford 200 mg ofcrude product. This was chromatographed on C18 reverse phase materialusing 20-40% acetonitrile/water, then 100% acetonitrile to afford 90 mgof the desired product, which was then recrystallized from ethylacetate/isooctane to yield 34 mg of pure carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, N-oxide; mass spectrum m/e=564 (M+Li).

EXAMPLE 13E

[0333]

[0334] Preparation of Carbamic acid.[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester

[0335] Part A:

[0336] A solution of 0.98 g (1.85 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-phenylmethylester in 3.8 mL of anhydrous DMF was added to 22 mg (7.4 mmol) of 80%sodium hydride in 2 mL of DMF. To this mixture was added 0.40 g (3.7mmol) of benzyl alcohol. After 2 hours, the solution was cooled to O C,water added, and then ethyl acetate. The organic layer was washed with5% cirtic acid, saturated sodium bicarbonate and brine, dried overmagnesium sulfate, filtered and concentrated to afford 0.90 g of crudematerial. This was chromatographed on basic alumina using 3%methanol/methylene chloride to afford 0.70 g of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine,cyclic carbamate; mass spectrum m/e=509 (M+H).

[0337] Part B:

[0338] To a solution of 0.65 g (1.28 mmol) of the cyclic carbamate frompart A in 15 mL of ethanol, was added 2.6 mL (6.4 mmol) of 2.5N sodiumhydroxide solution. After 1 hour at reflux, 4 mL of water was added andthe solution refluxed for an additional eight hours. The volatiles wereremoved, ethyl acetate added, and washed with water, brine, dried overmagnesium sulfate, filtered and concentrated to afford 550 mg ofcrude2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine.is Part C:

[0339] A solution of crude2R-hydroxy-3-[(2-methylpropyl)(4-benzyloxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 10 mL of ethanol was hydrogenated in the presence of 500 mg of a 10%palldium on carbon catalyst under 50 psig of hydrogen for 2 hours.

[0340] The catalyst was removed by filtration and the solvent removed invacuo to afford 330 mg of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine, mass spectrum m/e=393(M+H).

[0341] Part D:

[0342] To a solution of 320 mg (0.82 mmol) of the amine from part C in 6mL of DMF, was added 192 mg (0.76 mmol) ofN-hydroxysuccinimide-3-pyridylmethyl carbonate. After 15 hours at roomtemperature, the DMF was removed in vacuo, ethyl acetate added, washedwith water, brine, dried with magnesium sulfate, filtered andconcentrated to afford 390 mg of crude material. Chromatogrpahy onsilica gel using 50-80% ethyl acetate/hexane afforded 180 mg of carbamicacid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, mass spectrum m/e=528 (M+H).

EXAMPLE 13F

[0343]

[0344] Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidylmethyl ester

[0345] To a solution of 9.5 mg (0.09 mmol) of 5-pyrimidylcarbinol in 1mL of anhydrous acetonitrile at room temperature, was added 24 mg (0.09mmol) of N,N′-disuccinimidyl carbonate and 19.1 μL (0.24 mmol) ofpyridine. After stirring for 5 hours, 32 mg (0.08 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and the solution stirred for 48 hours. After concentration invacuo, methylene chloride was added, then washed with a 1:1 mixture ofsaturated sodium bicarbonate and brine, dried over magnesium sulfate,filtered and concentrated to give 27 mg of crude product. Chromatographyon silica gel using 2% methanol/methylene chloride afforded 22 mg of thedesired product, mass spectrum m/e=543 (M+H).

EXAMPLE 13G

[0346]

[0347] Preparation of carbamic acid.[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester.

[0348] Part A. Preparation of Ethyl 6-Aminonicotinate.

[0349] To a suspension of 1.3 g (9.4 mmol) 6-aminonicotinic acid in 100mL of ethanol, was bubbled in dry hydrochloric acid at 0 C, then thesolution was refluxed until all the solids dissolved. The solvents wereremoved under reduced pressure, the residue dissolved in ethyl acetate,washed with saturated sodium bicarbonate, brine and concentrated toafford 1.37 g of a white solid, m/e=166(M+H).

[0350] Part B. Preparation of Ethyl6-(tert-Butyloxycarbonylamino)nicotinate.

[0351] A mixture of 848 mg (5.1 mmol) of ethyl 6-aminonicotinate frompart A, 1.11 g (5.1 mmol) of di-tert-butylpyrocarbonate and 0.71 mL (5.1mmol) of triethylamine in 10 mL of anhydrous toluene was refluxed for 15hours. The solution was cooled, ethyl acetate added, washed withsaturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford 1.28 g of the desired ethyl6-(tert-butyloxycarbonylamino)nicotinate, m/e=267(M+H), which was useddirectly in the next step.

[0352] Part C. Preparation of6-(tert-Butyloxycarbonylamino)-3-pyridylmethanol.

[0353] To 4.6 mL (4.6 mmol) of a 1M solution of lithium aluminum hydridein diethyl ether at −40 C under a nitrogen atmosphere, was added aslution of 618 mg (2.3 mmol) of ethyl6-(tert-butyloxycarbonylamino)nicotinate from part B in 40 mL ofanhydrous tetrahydrofuran. After the addition, this was warmed to roomtemperature, stirred for 3 hours, cooled to 0 C, and 145 μL of water,145 μL of 20% sodium hydroxide solution and 290 μL of water weresuccessively added. To the resulting mixture was added 50 mL oftetrahydrofuran and stirring continued for 30 minutes. Anhydrousmagnesium sulfate was added, the solids removed via filtration and thefiltrate concentrated under reduced pressure to afford 460 mg of thedesired product, m/e=224(M+), which was used directly in the next step.

[0354] Part D. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester.

[0355] To a solution of 336 mg (1.5 mmol) of6-(tert-butyloxycarbonylamino)-3-pyridylmethanol from part C in 14 mL ofanhydrous acetonitrile at room temperature under a nitrogen atmosphere,was added 384 mg (1.5 mmol) of N,N′-disuccinimidyl carbonate and 364 μL(4.5 mmol) of anhydrous pyridine. After 4 hours, 406 mg (1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and stirring continued for 19 hours. The solvent was removedunder reduced pressure, ethyl acetate added, washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 702 mg of crude product. Chromatography on silicagel using 1% methanol/methylene chloride as eluent afforded 170 mg ofthe desired carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester, m/e=663(M+Li).

[0356] Part E. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester.

[0357] To 5 mL of 4N hydrochloric acid in dioxane at room temperature,was added 150 mg (0.23 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester from part D. Afterstirring at room temperature for 28 hours, the solvent was removed underreduced pressure, the resulting solids triturated with diethyl ether,then dissolved in ethyl acetate and saturated sodium bicarbonateslution, separated, the organic layer washed with brine, dried withmagnesium sulfate, filtered and concentrated. The residue waschromatographed on silica gel using 2.5% methanol/methylene chloride toyield 59 mg of the desired carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester, m/e=557(M+H).

EXAMPLE 13H

[0358]

[0359] Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester.

[0360] Part A. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester.

[0361] To a solution of 505 mg (2.25 mmol) of6-(tert-butyloxycarbonylamino)-3-pyridylmethanol from in 20 mL ofanhydrous acetonitrile at room temperature under a nitrogen atmosphere,was added 576 mg (2.25 mmol) of N,N′-disuccinimidyl carbonate and 546 μL(6.75 mmol) of anhydrous pyridine. After 1 hour, 837 mg (1.87 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and stirring continued for 3 hours. The solvent was removedunder reduced pressure, ethyl acetate added, washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 1.37 g of crude product. Chromatography on silicagel using 1% methanol/methylene chloride as eluent afforded 830 mg ofmaterial which was identified as a mixture of the desired carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester and the cycliccarbamate derived from the2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine.The mixture was very difficult to separate, so was used as is in thenext step.

[0362] Part B. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester.

[0363] To 830 mg of the mixture from part A, was added 50 mL of a 1:1mixture of trifluoroacetic acid and methylene chloride. After 2.5 hoursat room temperature, the solvent was removed under reduced pressure,ethyl acetate added, washed with saturated sodium bicarbonate, driedover magnesium sulfate, filtered and concentrated to afford 720 mg ofcrude material. This was chromatgraphed on silica gel using 5%methanol/ethyl acetate as eluent to yield 220 mg of product, which wasrecrystallized from methylene chloride/diethyl ether to afford 108 mg ofthe desired carbamic acid, [2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-S methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester, m/e=549 (M+Li).

EXAMPLE 13I

[0364]

[0365] Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester.

[0366] Part A. Preparation of tert-Butyldimethylsilyl6-(tert-butyldimethylsiloxy)nicotinate.

[0367] To a solution of 5.0 g (35.9 mmol) of 6-hydroxynicotinic acid in200 mL of anhydrous N,N-dimethylformamide at room temperature, was added8.56 g (125 mmol) of imidazole and then 13.5 g (89 mmol) oftert-butyldimethylsilyl chloride. After 20 hours, the solvent wasremoved under reduced pressure, ethyl acetate added, washed with water,5% citric acid, saturated sodium bicarbonate, brine, dried overanhydrous magnesium sulfate, filtered and concentrated to afford 10.5 gof crude material, m/e=368(M+H).

[0368] Part B. Preparation of3-(6-tert-butyldimethylsiloxy)pyridylcarbinol.

[0369] To 11 ml of 1M solution of lithium aluminum hydride in diethylether at −35 C under a nitrogen atmosphere, was added a solution of 2.0g (5.46 mmol) of prodtct from part A in 20 mL of anhydrous diethylether. After 30 minutes, the reaction was warmed to 0 C and stirred for40 minutes. The solution was then quenched by the careful addition of0.42 mL of water, 0.42 mL of 20% sodium hydroxide solution, and 0.84 mLof ater. Ethyl acetate was added, the precipate filtered and the organicphase concentrated to yield 0.93 g of crude3-(6-tert-butyldimethylsiloxy)pyridylcarbinol, which was used directlyin the next step.

[0370] Part C. Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester.

[0371] To a solution of 860 mg (3.6 mmol) of material from part B in 15mL of anhydrous acetonitrile, was added 919 mg (3.6 mmol) ofN,N′disuccinimidyl carbonate and 0.87 mL of pyridine. After 1 hour, 1.42g (3.5 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 14 hours at room temperature, the solvent was removedunder reduced pressure, the residue disslved in ethyl acetate, washedwith 5% citric acid, saturated sodium bicarbonate, brine, dried overmagnesium sukfate, filtered and concentrated to afford 2.1 g of crudematerial. This was directly deprotected by dissolving in 40 mL of 80%acetic acid/water and stirring for 2 hours. The solvents were removedunder reduced pressure, the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate, brine, dried over magnesium sulfate,filtered and concentrated to afford 1.7 g of crude product. This waschromatographed on silica gel using 50-100% ethyl acetate/hexane toprovide a fraction of 0.19 g of fairly pure material, which was furtherpurified by reverse phase chromatography using 15-40% acetonitrile/water(0.05% trifluoroacetic acid) to provide 120 mg of the desired carbamicacid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester, m/e=558(M+H).

EXAMPLE 13J

[0372]

[0373] Preparation of carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl],5-pyrimidylmethyl ester.

[0374] To a solution of 237 mg (2.15 mmol) of 5-pyrimidylcarbinol in 24mL of anhydrous acetonitrile, was added 602 mg (2.35 mmol) ofN,N′-disuccinimidyl carbonate and then 0.47 mL of pyridine. Afterstirring for 4.5 hours, 766 mg (1.96 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring for 19 hours, the solvent was removed underreduced pressure, ethyl acetate added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford 1.0 g of crude material.Chromatography on silica gel using 50-100% ethyl acetate/hexane aseluent afforded 450 mg of the desired carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidylmethyl ester, m/e=529 (M+H)

EXAMPLE 14

[0375]

[0376] Preparation ofphenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]-carbonyl]-3-oxopropyl]carbamate

[0377]Phenylmethyl[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-carbamate(200 mg, 0.40 mmol) was deprotected by hydrogenation over 10% palladiumon carbon and the resulting free amine was coupled withN-CBZ-L-asparagine (157 mg, 0.42 mmol) in the presence ofN-hydroxybenzotriazole (114 mg, 0.84 mmol) and EDC (130 mg, 0.67 mmol)to givephenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamateas a solid. Anal. Calcd for C₃₁H₃₈N₄O₇S.0.2H₂O: C,60.61; H,6.30; N,9.12.Found: C,60.27; H,6.16; N,8.93.

EXAMPLE 15A

[0378]

[0379] Preparation ofN1-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-N-4-methyl-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide

[0380] Part A:

[0381] N2-[(1,1-dimethylethoxy)carbonyl]-N-methyl-L-asparagine wasprepared from Boc-L-aspartic acid alpha-benzyl ester (1.0 g, 3.09 mmol),methylamine.HCl (209 mg, 3.09 mmol), EDC (711 mg, 3.7 mmol),1-hydroxybenzotriazole (627 mg, 4.63 mmol), and N-methylmorpholine (0.7mL, 6.3 mmol), in DMF (20 mL). After stirring overnight at r.t., thereaction mixture was diluted with ethyl acetate, washed with water, sat.sodium bicarbonate, 5% citric acid, brine, dried over magnesium sulfateand concentrated to an oil. The oil was taken up in 20 mL dry ethanol,and hydrogenated in the presence of 10% w/w of 10% Pd on C atatmospheric pressure and room temperature overnight. The mixture wasfiltered through Celite and concentrated to a white solid foam, 670 mg.

[0382] Part B:

[0383] A solution of phenylmethyl [2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate (310 mg, 0.59mmol) in methanol (10 mL) was hydrogenated over 10% palladium on carbonfor 3 h., filtered through diatomaceous earth and concentrated to givethe product as an oil (214 mg). This free amine (208 mg, 0.53 mmol) wascoupled with N2-[(1,1-dimethylethoxy)-carbonyl]-N-methyl-L-asparagine(137 mg, 0.56 mmol) in the presence of N-hydroxybenzotriazole (102 mg,0.76 mmol) and EDC (130 mg, 0.67 mmol) to yield 290 mg ofN1[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)-amino]-N-4-methyl-1S-(phenylmethyl)propyl]-2S-[(1,1-dimethylethoxy-carbonyl)amino]butanediamide.

[0384] Part C:

[0385]N1[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-N-4-methyl-1S-(phenylmethyl)propyl]-2S-[(1,1-dimethylethoxycarbonyl)-amino]butanediamide (270 mg, 0.43 mmol) was stirred in 4N HCl in dioxane (5 mL) atr.t. for 0.5 h. Solvent and excess reagent were evaporated to dryness.The product was dried in vacuo. This material (125 mg, 0.225 mmol) wasthen reacted with 2-quinoline carboxylic acid N-hydroxysuccimide ester(61 mg, 0.225 mmol), N-methylmorpholine (50 uL, 0.45 mmol) in methylenechloride (2 mL) for 3 h. The productN1[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-N-4-methyl-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)-amino]butanediamide was purified by silica gel chromatography. Anal. Calcd forC₃₆H₄₃N₅O₆S.0.2H₂O: C,63.83; H,6.45; N,10.34. Found: C,63.64; H,6.40;N,10.34.

EXAMPLE 15B

[0386] Following the procedures set forth above, the following compoundwas also prepared:

[0387] Preparation of Carbamic acid,[3-[[2-hydroxy-3-[(3-methylbutyl)(phenylsufonyl)amino]-1-(phenylmethyl)propyl]amino]-2-methyl-3-oxopropyl]-,(4-methoxyphenyl)methyl ester, [1S-[1R*(S*) 2S*]]-

[0388] Thus, 4.10 g, (7.8 mmol), of Carbamic acid,[2R-hydroxy-3-[(3-methylbutyl)(phenylsulphonyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester, [R-(R*,S*)]- was hydrogenated in a solution ofmethanol and ethanol using catalytic Pd/C 10% at 50 psig hydrogen for 3hours. The catalyst was filtered and the solvents removed in vacuo toyield 3.0 grams of free amine.

[0389] In a separate flask, 2.09 g, (7.8 mmol), of N-Moz-AMBA was addedto 10 mL of dimethylformamide and 1.58 g, (1.5 equiv.), ofN-hydroxybenzoltriazole and the solution was cooled to 5 degrees C. Tothis solution was added 1.49 g, (7.8 mmol), of EDC and the solutionstirred for 30 min. To this was added the free amine in 10 mL ofdimethylformamide, and the reaction was stirred for 20 hours. Thesolvent was removed by evaporation and the crude material waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The ethyl acetate layer was washed with 5% potassiumhydrogen sulfate and brine, dried over magnesium sulfate, filtered andconcentrated to yield 2.58 grams of pure product after recrystallizationfrom ethyl acetate, ether, and hexanes. 52% yield.

EXAMPLE 16A

[0390]

[0391] Preparation of Carbamic acid.[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester.

[0392] To a solution of 406 mg (1.0 mmol) of[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine in 5.0 mL of dichloromethane containing 150 mg (1.5 mmol) oftriethylamine was added 280 mg (1.22 mmol) ofN-succinimidyl-3-(S)-tetrahydrofuranyl carbonate and the reacton mixturewas stirred for 2 hours, an additonal 136 mg (0.3 mmol) of amine wasadded to the mixture and the solution stirred another 2 hours. Thecontents were diluted with 50 mL of ethyl acetate and washed with 5%aqueous citric acid, saturated sodium bicarbonate, and brine, then driedover magnesium sulfate, filtered and concentrated to yield 330 mg ofcrude product. Purification by silica gel chromatography using an eluantof 1:1 to 2:1 ethyl acetate/hexanes gradient provided Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester as a white solid. m/z=521 (M+H) calc.521.2311 obs. 521.2311

EXAMPLE 16B

[0393]

[0394] Preparation of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester,

[0395] To a solution of 435 mg (1.0 mmol) of[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine in 3.0 mL of dimethylformamide was added 225 mg (0.98 mmol)of N-succinimidyl-3-(S)-tetrahydrofuranyl carbonate and the solution wasstirred overnight. The mixture was diluted with 50 mL of ethyl acetateand washed with 5% aqueous citric acid, saturated sodium bicarbonate,and brine, dried over magnesium sulfate, filtered and concentrated toyield 515 mg of crude product. Purificaton by silica gel chromatographyusing and eluant of 1:1 ethyl acetate:hexanes provided 315 mg ofCarbamic acid, [2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester, as a white solid. m.p=HRMS calc.507.2165, obs. 507.2155

EXAMPLE 16C

[0396]

[0397] Preparation of Carbamic acid,[2R-hydroxy-3-[(4-methoxyyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester,

[0398] To a solution of 215 mg (2.0 mmol) of 3-S-hydroxythiophene, 415μL of anhydrous pyridine, and 2 mL of dry acetonitrile was added 512 mg(2.0 mmol) of N,N′-Dimethylsuccinimidyl carbonate and this suspensionwas stirred for 45 minutes. To this clear solution was added a solutionof 700 mg (1.7 mmol) of[2R-hydroxy-3-[[(4-methoxyyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminein 2.0 mL of acetonitrile and stirred for 12 hours. the contents wereconcentrated, and the residue was partitioned between ethyl acetate and5% aqueous potassium hydrogen sulfate. The organic layer was washed withsaturated sodium bicarbonate and then brine, dried over sodium sulfate,filtered and concentrated to yield 780 mg of crude material. Purificatonby silica gel chromatograpy using an eluant of 10:10:1 ethylacetate:hexane:methanol provided 520 mg of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester, as a crystalline white solid.m.p.=162-3° C., m/z=553 (M+H)

EXAMPLE 16D

[0399]

[0400] Preparation of Carbamic Acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(s)-1,1-dioxotetrahydrothiophen-3-yl-ester,

[0401] To a solution of 270 mg (0.5 mmol) of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester in 30 mL of dichloromethane was added400 mg (1.2 mmol) of m-chloroperbenzoic acid (50 wt %) and the mixturewas stirred for 12 hours. The contents were diluted with 10 mL of 10%aqueous sodium metabisulfite and stirred for 30 minutes. The organiclayer was washed with saturated sodium bicarbonate, dried over sodiumsulfate, filtered and concentrated to yield 290 mg of crude product.Purification by silica gel chromatography using an eluant of 10:10:1ethyl acetate:hexane:methanol provided 260 mg of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester, as a white crystallinesolid. m.p.=69° C., m/z=569 (M+H)

EXAMPLE 16E

[0402]

[0403] Preparation of Carbamic Acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester.

[0404] To a solution of 125 mg (1.2 mmol) of 3-S-hydroxythiophene, 250μL of anhydrous pyridine, and 1 mL of dry acetonitrile was added 307 mg(1.2 mmol) of N,N′-Dimethylsuccinimidyl carbonate and this suspensionwas stirred for 45 minutes. To this clear solution was added a solutionof 445 mg (1.0 mmol)[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminein 1.0 mL of acetonitrile and stirred for 12 hours. the contents wereconcentrated, and the residue was partitioned between ethyl acetate and5% aqueous potassium hydrogen sulfate. The organic layer was washed withsaturated sodium bicarbonate and then brine, dried over sodium sulfate,filtered and concentrated to yield 460 mg of crude material. Purificatonby silica gel chromatograpy using an eluant of 10:10:1 ethylacetate:hexane:methanol provided 235 mg of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester, as a crystalline white solid.m.p.=184-85° C., m/z=529 (M+Li)

EXAMPLE 16F

[0405]

[0406] Preparation of Carbamic Acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S.)-1.1-dioxotetrahydrothiophen-3-yl-ester,

[0407] To a solution of 125 mg (0.24 mmol) of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester in 30 mL of dichloromethane was added240 mg (0.7 mmol) of m-chloroperbenzoic acid (50 wt %) and the mixturewas stirred for 12 hours. The contents were diluted with 5 mL of 10%aqueous sodium metabisulfite and stirred for 30 minutes. The organiclayer was washed with saturated sodium bicarbonate, dried over sodiumsulfate, filtered and concentrated to yield 110 mg of crude product.Purification by silica gel chromatography using an eluant of 1:1 to 2:1ethyl acetate:hexane:methanol provided 100 mg of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester, as a white crustallinesolid, m.p.=190-1° C., m/z=561 (M+Li)

EXAMPLE 17A

[0408] Carbamic Acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](methylpropyl)amino]-1S-(phenylmethyl)propyl]-0.5-(thiazolyl)methylester can be Prepared According to the Following Procedures.

[0409] To a solution of 172 mg (1.5 mmol) of 5-hydroxymethylthiazole in14 mL of anhydrous acetonitrile at room temperatures under a nitrogenatmosphere, is added 384 mg (1.5 mmol) of N,N′-disuccinimidyl carbonateand 364 μL (4.5 mmol) of anhydrous pyridine. After about 4 hourse, 406mg (1 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine is addedand stirring would be continued for approximately 19 hours. The solventwould be removed under reduced pressure, ethyl acetate added, washedwith saturated sodium bicarbonate, brine, dried over magnesium sulfate,filtered and concentrated to afford crude product. The desired carbamicacid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methylester could be isolated in pure form through chromatography on silicagel using 50-100% ethyl acetate/hexane as eluent.

EXAMPLE 17B

[0410] Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methylester can be Prepared According to the Following Procedure.

[0411] To a solution of 482 mg (4.3 mol) of 5-(hydroxymethyl)thiazole in48 mL of anhydrous acetonitrile, is added 1.2 g (4.7 mmol) ofN,N′-disuccinimidyl carbonate and then 0.94 mL of pyridine. Afterstirring for about 4 to 5 hours, 1.53 g (3.92 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamineis added. After stirring for approximately 19 hours, the solvent wouldbe removed under reduced pressure, theyl acetate added, washed with 5%citric acid, saturated sodium bicarbonate, brine, dried over anhydrousmagnesium sulfate, filtered and concentrated to afford crude product.The desired carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)pro,5-(thiazolyl)methylester could be isolated in pure form through chromatography on silicagel using 50-100% ethyl acetate/hexane as eluent.

EXAMPLE 18

[0412] Following the procedures of Examples 1-16, the compounds shown inTables 3, 5A and 5B were prepared and in Tables 4 through 17 can beprepared. TABLE 3

Entry No. R R¹ R³ R⁴ 1 Cbz t-Butyl i-Amyl Methyl 2 N,N-Dimethylglycinet-Butyl i-Amyl Methyl 3 Cbz i-Propyl i-Amyl Phenyl 4 Cbz sec-Butyli-Amyl Phenyl 5 Cbz CH₂C(O)NH₂ n-Propyl Phenyl 6 N-Methylglycine t-Butyli-Amyl Phenyl 7 Cbz t-Butyl i-Butyl Phenyl 8 N,N-Dimethylglycine t-Butyli-Amyl Phenyl 9 N-Methylglycine t-Butyl i-Amyl Phenyl 10N,N-Dimethylglycine t-Butyl i-Butyl (4-OCH₃)Phenyl 11 N-Methylglycinet-Butyl i-Butyl (4-OCH₃)Phenyl

[0413] TABLE 4

Entry No. R R³ R⁴ 1 Cbz^(a) CH₃ n-Butyl 2 Cbz i-Butyl CH₃ 3 Cbz i-Butyln-Butyl 4 Q^(b) i-Butyl n-Butyl 5 Cbz i-Propyl n-Butyl 6 Q i-Propyln-Butyl 7 Cbz C₆H₅ n-Butyl 8 Cbz

n-Butyl 9 Cbz

n-Butyl 10 Q

n-Butyl 11 Cbz

n-Butyl 12 Cbz i-Butyl n-Propyl 13 Cbz i-Butyl —CH₂CH(CH₃)₂ 14 Cbz

n-Butyl 15 Cbz

i-Propyl 16 Cbz

—CH₂CH₂CH(CH₃)₂ 17 Cbz i-Butyl —CH₂CH₃ 18 Cbz i-Butyl —CH(CH₃)₂ 19 Cbzi-Butyl

20 Q -Butyl

21 Cbz

—(CH₂)₂CH(CH₃)₂ 22 Cbz (CH₂)₂CH(CH₃)₂ —CH(CH₃)₂ 23 Q i-Butyl —CH(CH₃)₂24 Cbz i-Butyl —C(CH₃)₃ 25 Q i-Butyl —C(CH₃)₃ 26 Cbz

—C(CH₃)₃ 27 Q

—C(CH₃)₃ 28 Cbz —(CH₂)₂CH(CH₃)₂ —C(CH₃)₃ 29 Q —(CH₂)₂CH(CH₃)₂ —C(CH₃)₃30 Cbz —CH₂C₆H₅ —C(CH₃)₃ 31 Q —CH₂C₆H₅ —C(CH₃)₃ 32 Cbz —(CH₂)₂C₆H₅—C(CH₃)₃ 33 Cbz —(CH₂)₂C₆H₅ —C(CH₃)₃ 34 Cbz n-Butyl —C(CH₃)₃ 35 Cbzn-Pentyl —C(CH₃)₃ 36 Cbz n-Hexyl —C(CH₃)₃ 37 Cbz

—C(CH₃)₃ 38 Cbz —CH₂C(CH₃)₃ —C(CH₃)₃ 39 Q —CH₂C(CH₃)₃ —C(CH₃)₃ 40 Cbz

—C(CH₃)₃ 41 Cbz —CH₂C₆H₅OCH₃(para) —C(CH₃)₃ 42 Cbz

—C(CH₃)₃ 43 Cbz

—C(CH₃)₃ 44 Cbz —(CH₂)₂C(CH₃)₃ —C(CH₃)₃ 45 Q —(CH₂)₂C(CH₃)₃ —C(CH₃)₃ 46Cbz —(CH₂)₄OH —C(CH₃)₃ 47 Q —(CH₂)₄OH —C(CH₃)₃ 48 Q

—C(CH₃)₃ 49 Q

—C(CH₃)₃ 50 Cbz —CH₂CH(CH₃)₂ —C₆H₅ 51

—CH₂CH(CH₃)₂ —C₆H₅ 52

—CH₂CH(CH₃)₂ —C₆H₅ 53

—CH₂CH(CH₃)₂ —C₆H₅ 54

—CH₂CH(CH₃)₂ —C₆H₅ 55

—CH₂CH(CH₃)₂ —C₆H₅ 56

—CH₂CH(CH₃)₂ —C₆H₅ 57

—CH₂CH(CH₃)₂ —C₆H₅ 58

—CH₂CH(CH₃)₂ —C₆H₅ 59

—CH₂CH(CH₃)₂ —C₆H₅ 60

—CH₂CH(CH₃)₂ —C₆H₅ 61

—CH₂CH(CH₃)₂ —C₆H₅ 62

—CH₂CH(CH₃)₂ —C₆H₅ 63

—CH₂CH(CH₃)₂ —C₆H₅ 64

—CH₂CH(CH₃)₂ —C₆H₅ 65

—CH₂CH(CH₃)₂ —C₆H₅ 66

—CH₂CH(CH₃)₂ —C₆H₅ 67

—CH₂CH(CH₃)₂ —C₆H₅ 68

—CH₂CH(CH₃)₂ —C₆H₅ 69

—CH₂CH(CH₃)₂ —C₆H₅ 70 Q —CH₂Ph —Ph 71 Q

—Ph 72 Q

—Ph 73 Q

—Ph 74 Q

—Ph 75 Q

—Ph 76 Q —CH₂CH═CH₂ —Ph 77 Q

—Ph 78 Q

—Ph 79 Q —CH₂CH₂Ph —Ph 80 Q —CH₂CH₂CH₂CH₂OH —Ph 81 Q —CH₂CH₂N(CH₃)₂ —Ph82 Q

—Ph 83 Q —CH₃ —Ph 84 Q —CH₂CH₂CH₂SCH₃ —Ph 85 Q —CH₂CH₂CH₂S(O)₂CH₃ —Ph 86Q —CH₂CH₂CH₂CH(CH₃)₂

87 Q —CH₂CH₂CH(CH₃)₂

88 Q —CH₂CH₂CH(CH₃)₂ —CH₂CH₂CH₃ 89 Q —CH₂CH₂CH₂CH(CH₃)₂ —CH₃ 90 Q—CH₂CH₂CH(CH₃)₂

91 Q —CH₂CH₂CH(CH₃)₂

92 Q —CH₂CH₂CH(CH₃)₂

93 Q —CH₂CH₂CH(CH₃)₂

94 Q —CH₂CH₂CH(CH₃)₂

95 Q —CH₂CH₂CH(CH₃)₂

96 Q —CH₂CH₂CH(CH₃)₂

97 Q —CH₂CH₂CH(CH₃)₂

98 Q —CH₂CH₂CH(CH₃)₂

99 Q —CH₂CH₂CH(CH₃)₂

100 Q —CH₂CH₂CH(CH₃)₂

101 Q —CH₂CH₂CH(CH₃)₂

102 Q —CH₂CH₂CH(CH₃)₂

103 Q —CH₂CH(CH₃)₂

104 Q —CH₂CH(CH₃)₂

105 Q —CH₂CH(CH₃)₂

106 Q —CH₂CH₂CH₃

107 Q —CH₂CH₂CH₂CH₃

[0414] TABLE 5

Entry A R³ R⁴ 1 Cbz-Val i-amyl —C₆H₅ 2 Cbz-Leu i-amyl —C₆H₅ 3 Cbz-11ei-amyl —C₆H₅ 4 Ac-D-homo-Phe i-Bu methyl 5 Qui-Om(g-Cbz)

—C₆H₅ 6 Cbz-Asn —CH₂CH═CH₂ —C₆H₅ 7 Acetyl-t-BuGly i-amyl —C₆H₅ SAcetyl-Phe i-amyl —C₆H₅ 9 Acetyl-Ile i-amyl —C₆H₅ 10 Acetyl-Leu i-amyl—C₆H₅ 11 Acetyl-His i-amyl —C₆H₅ 12 Acetyl-Thr i-amyl —C₆H₅ 13Acetyl-NHCN(C(CH₃)₂(SCH₃))C(O)— i-amyl —C₆H₅ 14 Cbz-Asn i-amyl —C₆H₅ 15Cbz-Ala i-amyl —C₆H₅ 16 (N,N-dimethylglycinyl)Val i-amyl —C₆H₅ 17(N-methylglycinyl)Val i-amyl —C₆H₅ 18 (N,N-dimethylglycinyl)Ile i-amyl—C₆H₅ 19 (N-methylglycinyl)Ile i-amyl —C₆H₅ 20 Cbz-Ala i-amyl —C₆H₅ 21Cbz-beta-cyanoAla i-amyl —C₆H₅ 22 Cbz-t-BuGly i-amyl —C₆H₅ 23 Q-t-BuGlyi-amyl —C₆H₅ 24 Q-SCH₃Cys i-amyl —C₆H₅ 25 Cbz-SCH₃Cys i-amyl —C₆H₅ 26Q-Asp i-amyl —C₆H₅ 27 CbZ-(NHCH(C(CH₃)₂(SCH₃))C(O)— i-amyl —C₆H₅ 28Cbz-EtGly i-amyl —C₆H₅ 29 Cbz-PrGly i-amyl —C₆H₅ 30 Cbz-Thr i-amyl —C₆H₅31 Q-Phe i-amyl —C₆H₅ 32 Cbz-Phe i-amyl —C₆H₅ 33

i-Butyl —C₆H₄

[0415] TABLE 5A Entry

MASS MEASUREMENT CALC R³ R⁴ R⁷ MOL FORM M + H FOUND  1

C₂₇H₃₈N₂O₅S 503.2661 503.2624  2

C₂₈H₄₀N₂O₅S 517.2736 517.2777  3

C₂₉H₄₂N₂O₅S 531.2893 531.2916  4

C₃₂H₄₀N₂O₅S 565.2736 565.2731  5

C₃₀H₃₅N₃O₅S 550.2376 550.2427 MASS MEASUREMENT R³ R⁴ R⁷ MOL FORM CALCFOUND  6

C₃₀H₃₈N₂O₅S 539(M + H) 539  7

C₂₉H₃₆N₂O₅S ? ?  8 C₃₀H₃₈N₂O₅S 539.2580 (M + H) 539.2591 MASSMEASUREMENT CALC R³ R⁴ R⁷ MOL FORM M + H FOUND  9

C₂₇H₃₃N₃O₅S 512.2219 512.2271 10

C₂₈H₃₅N₃O₅S 526.2376 526.2388 11

C₂₇H₃₃N₃O₅S 512.2219 512.2287 12

C₂₈H₃₃N₂O₅ClS 545.1877 545.1887 13

C₃₀H₃₈N₂O₅S 539.2580 539.2592 14

C₃₁H₄₀N₂O₅S 553.2736 553.2714 15

C₃₀H₃₈N₂O₅S 539.2580 539.2632 16

C₃₀H₃₈N₂O₅S 539 (M + H) 539 MASS MEASUREMENT R³ R⁴ R⁷ MOL FORM CALCFOUND 17

C₂₉H₃₆N₂O₇S₂ 589.2042 (M + H) 589.2086 18

C₂₉H₃₆N₂O₇S₂ 595.2124 (M + Li) 595.2103 19

C₂₉H₃₆N₂O₇S₂ 595.2124 (M + Li) 595.2191 20

C₃₀H₃₈N₂O₇S₂ 609.2281 (M + Li) 609.2313 21

C₃₀H₃₈N₂O₇S₂ 603.2199 (M + H) 603.2247 22

C₃₀H₃₈N₂O₇S₂ 603.2199 (M + H) 603.2266 MASS MEASUREMENT CALC R³ R⁴ R⁷MOL FORM M + H FOUND 23

24

C₂₇H₃₂N₂O₄S 481.2161 481.2213 25

C₂₈H₃₅N₂O₅S 511.2267 511.2319 26

C₂₉H₃₆N₂O₅S 525.2423 525.2469 27

C₂₉H₃₆N₂O₅S 525.2428 525.2464 28

C₂₉H₃₆N₂O₅S 525.2423 525.2432 29

C₂₉H₃₆N₂O₆S 541.2372 541.2332 30

C₂₉H₃₆N₂O₆S 541.2372 541.2355 31

C₂₉H₃₆N₂O6_(S) 541.2372 541.2329

[0416] TABLE 5B

Entry A Molecular Formula Mass Spectrum

C₂₉H₃₅N₃O₇S 576 (M + Li)

C₂₉H₃₇N₃O₅S 540 (M + H)

C₃₁H₄₁N₃O₅S 568 (M + H)

C₂₉H₃₅N₃O₇S 570 (M + H)

C₂₉H₃₇N₃O₅S 540 (M + H)

C₃₁H₄₁N₃O₅S 568 (M + H)

C₂₉H₃₅N₃O₇S 570 (M + H)

C₂₉H₃₇N₃O₅S 546 (M + Li)

C₃₁H₄₁N₃O₅S 574 (M + Li)

[0417] TABLE 6

Entry R¹ 1 CH₂SO₂CH₃ 2 (R)—CH(OH)CH₃ 3 CH(CH₃)₂ 4 (R,S)CH₂SOCH₃ 5CH₂SO₂NH₂ 6 CH₂SCH₃ 7 CH₂CH(CH₃)₂ 8 CH₂CH₂C(O)NH₂ 9 (S)—CH(OH)CH₃ 10—CH₂C≡C—H

[0418] TABLE 7

Entry R² A 1 n-Bu Cbz-Asn 2 cyclohexylmethyl Cbz-Asn 3 n-Bu Boc 4 n-BuCbz 5 C₆H₅CH₂ Boc 6 P-F-C₆H₅CH₂ Cbz 7 C₆H₅CH₂ benzoyl 8 cyclohexylmethylCbz 9 n-Bu Q-Asn 10 cyclohexylmethyl Q-Asn 11 C₆H₅CH₂ Cbz-Ile 12 C₆H₅CH₂Q-Ile 13 P-F-C₆H₅CH₂ Cbz-t-BuGly 14 C₆H₅CH₂ Q-t-BuGly 15 C₆H₅CH₂ Cbz-Val16 C₆H₅CH₂ Q-Val 17 2-naphthylmethyl Cbz-Asn 18 2-naphthylmethyl Q-Asn19 2-naphthylmethyl Cbz 20 n-Bu Cbz-Val 21 n-Bu Q-Val 22 n-Bu Q-Ile 23n-Bu Cbz-t-BuGly 24 n-Bu Q-t-BuGly 25 p-F(C₆H₄)CH₂ Q-Asn 26 p-F(C₆H₄)CH₂Cbz 27 p-F(C₆H₄)CH₂ Cbz-Asn 28 C₆H₅CH₂ Cbz-propargylglycine 29 C₆H₅CH₂Q-propargylglycine 30 C₆H₅CH₂ acetylpropargylglycine

[0419] TABLE 8

Entry R³ R⁴ 1 —CH₂CH(CH₃)₂ —C(CH₃)₂ 2 —CH₂CH₂CH(CH₃)₂

3 —CH₂CH₂CH(CH₃)₂

4 —CH₂CH₂CH(CH₃)₂

5 —CH₂CH₂CH(CH₃)₂

[0420] TABLE 9

Entry R R¹ 1

—CH₃ 2

—CH₃ 3

—CH(CH₃)₂ 4

—CH(CH₃)₂ 5

—C(CH₃)₃ 6

—CH₃ 7

—CH₃ 8

—CH₃ 9

—CH₃ 10

—CH₃ 11

—CH₃ 12

—CH₃ 13

—CH₃ 14

—CH₃ Entry 15

16

[0421] TABLE 10

Entry R¹ R^(1′) R^(1″) R 1 H H H

2 H H H

3 H CH₃ H

4 H CH₃ CH₃

5 H H CO₂CH₃

6 H H H

7 H H H

8 H H CONH₂ Cbz 9 H H CONH₂ 2-quinolinylcarbonyl

[0422] TABLE 11

Entry R R′ X 1 R = H R′ = H X = H 2 R = Me R′ = Me X = H 3 R = H R′ = MeX = H 4 R = Me R′ = Me X = F 5 R = H R′ = Me X = F 6 R = Cbz R′ = Me X =H 7 R = H R′ = Bz X = H 8 R + R′ = pyrrole X = H

[0423] TABLE 12

Entry Acyl Group (R) 1 benzyloxycarbonyl 2 tert-butoxycarbonyl 3 acetyl4 2-quinoylcarbonyl 5 phenoxyacetyl 6 benzoyl 7 methyloxaloyl 8 pivaloyl9 trifluoracetyl 10 bromoacetyl 11 hydroxyacetyl 12 morpholinylacetyl 13N,N-dimethylaminoacetyl 14 N-benzylaminoacetyl 15 N-phenylaminoacetyl 16N-benzyl-N-methylaminoacetyl 17 N-methyl-N-(2-hydroxyethyl)aminoacetyl18 N-methylcarbamoyl 19 3-methylbutyryl 20 N-isobutylcarbamoyl 21succinoyl (3-carboxypropionyl) 22 carbamoyl 23 N-(2-indanyl)aminoacetyl

[0424] TABLE 13

Entry R³ R⁴ 1 —CH₃ -n-Butyl 2 -i-Butyl —CH₃ 3 -i-Butyl -n-Butyl 4-i-Propyl -n-Butyl 5 —C₆H₅ -n-Butyl 6

-n-Butyl 7

-n-Butyl 8

-n-Butyl 9 -i-Butyl -n-Propyl 10 -1-Butyl —CH₂CH(CH₃)₂ 11

-n-Butyl 12

-i-Propyl 13

—CH₂CH₂CH(CH₃)₂ 14 i-Butyl —CH₂CH₃ 15 1-Butyl —CH(CH₃)₂ 16 i-Butyl

17

—(CH₂)₂CH(CH₃)₂ 18 (CH₂)₂CH(CH₃)₂ —CH(CH₃)₂ 19 i-Butyl —CH(CH₃)₂ 20i-Butyl —C(CH₃)₃ 21

—C(CH₃)₃ 22 —(CH₂)₂CH(CH₃)₂ —C(CH₃)₃ 23 —CH₂C₆H₅ —C(CH₃)₃ 24 —(CH₂)₂C₆H₅—C(CH₃)₃ 25 n-Butyl —C(CH₃)₃ 26 n-Pentyl —C(CH₃)₃ 27 n-Hexyl —C(CH₃)₃ 28

—C(CH₃)₃ 29 —CH₂C(CH₃)₃ —C(CH₃)₃ 30

—C(CH₃)₃ 31 —CH₂C₆H₅OCH₃(para) —C(CH₃)₃ 32

—C(CH₃)₃ 33

—C(CH₃)₃ 34 —(CH₂)₂C(CH₃)₃ —C(CH₃)₃ 35 —(CH₂)₄OH —C(CH₃)₃ 36

—C(CH₃)₃ 37

—C(CH₃)₃ 38 —CH₂CH(CH₃)₂ —C₆H₅ 39 i-amyl —CH₂C(CH₃)₃ 40

—CH₂C(CH₃)₃ 41

—CH₂C(CH₃)₃ 42 i-butyl —CH₂C(CH₃)₃ 43 —CH₂Ph —Ph 44

—Ph 45

—Ph 46

—Ph 47

—Ph 48

—Ph 49 —CH₂CH═CH₂ —Ph 50

—Ph 51

—Ph 52 —CH₂CH₂Ph —Ph 53 —CH₂CH₂CH₂CH₂OH —Ph 54 —CH₂CH₂N(CH₃)₂ —Ph 55

—Ph 56 —CH₃ —Ph 57 —CH₂CH₂CH₂SCH₃ —Ph 58 —CH₂CH₂CH₂S(O)₂CH₃ —Ph 59—CH₂CH₂CH(CH₃)₂

60 —CH₂CH₂CH(CH₃)₂

61 —CH₂CH₂CH(CH₃)₂ —CH₂CH₂CH₃ 62 —CH₂CH₂CH(CH₃)₂ —CH₃ 63 —CH₂CH₂CH(CH₃)₂

64 —CH₂CH₂CH(CH₃)₂

65 —CH₂CH₂CH(CH₃)₂

66 —CH₂CH₂CH(CH₃)₂

67 —CH₂CH₂CH(CH₃)₂

68 —CH₂CH₂CH(CH₃)₂

69 —CH₂CH₂CH(CH₃)₂

70 —CH₂CH₂CH(CH₃)₂

71 —CH₂CH₂CH(CH₃)₂

72 —CH₂CH₂CH(CH₃)₂

73 —CH₂CH₂CH(CH₃)₂

74 —CH₂CH₂CH(CH₃)₂

75 —CH₂CH(CH₃)₂

76 —CH₂CH(CH₃)₂

77 —CH₂CH(CH₃)₂

78 —CH₂CH(CH₃)₂

79 —CH₂CH₂CH₃

80 —CH₂CH₂CH₂CH₃

[0425] TABLE 14

Entry R¹ R³ 1 C(CH₃)₃ CH₂CH₂CH(CH₃)₂ 2 CH₂C≡CH CH₂CH₂CH(CH₃)₂ 3C(CH₃)₂(SCH₃) CH₂CH₂CH(CH₃)₂ 4 C(CH₃)₂(S[O]CH₃) CH₂CH₂CH(CH₃)₂ 5C(CH₃)₂(S[O]₂CH₃) CH₂CH₂CH(CH₃)₂ 6 C(CH₃)₃ CH₂CH(CH₃)₂ 7 C(CH₃)₃

8 CH(CH₃)₂ CH₂CH(CH₃)₂ 9 CH(CH₂CH₃)(CH₃) CH₂CH(CH₃)₂

[0426] TABLE 14A

Entry R¹ R³ 1 C(CH₃)SCH₃ CH₂CH₂CH(CH₃)₂

[0427] TABLE 15

A

[0428] TABLE 16

A R

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

[0429] TABLE 17

A Group B Group

[0430] TABLE 17A

A Group B Group

n = 0, 1, or 2

R′ = OH, methoxy, benzyloxy, —C(NH₂)═NOH, —C(NH₂)═NH

R″ = H or lower alkyl.

[0431] TABLE 17B

[0432] TABLE 17B-1

[0433] TABLE 17B-2

EXAMPLE 19

[0434] The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein disclosed inhibited the HIV enzyme. Thepreferred compounds of the present invention and their calculated IC₅₀(inhibiting concentration 50%, i.e., the concentration at which theinhibitor compound reduces enzyme activity by 50%) values are shown inTables 18 through 21. The enzyme method is described below. Thesubstrate is 2-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control isMVT-101 (Miller, M. et al, Science, 246, 1149 (1989)] The assayconditions are as follows: Assay buffer: 20 mM sodium phosphate, pH 6.4 20% glycerol  1 mM EDTA  1 mM DTT 0.1% CHAPS

[0435] The above described substrate is dissolved in DMSO, then diluted10 fold in assay buffer. Final substrate concentration in the assay is80 μM.

[0436] HIV protease is diluted in the assay buffer to a final enzymeconcentration of 12.3 nanomolar, based on a molecular weight of 10,780.

[0437] The final concentration of DMSO is 14% and the finalconcentration of glycerol is 18%. The test compound is dissolved in DMSOand diluted in DMSO to 10× the test concentration; 10 μl of the enzymepreparation is added, the materials mixed and then the mixture isincubated at ambient temperature for 15 minutes. The enzyme reaction isinitiated by the addition of 40 μl of substrate. The increase influorescence is monitored at 0.4 time points (0, 8, 16 and 24 minutes)at ambient temperature. Each assay is carried out in duplicate wells.

[0438] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples. TABLE 18A Entry Compound IC₅₀(nanomolar) 1

16 2

1.5 3

1.4 4

27 5

19 6

10 7

3.6 8

4.2 9

3.5 10

100 11

81 12

20

[0439] TABLE 19B Ex. Table Entry IC₅₀ (uM) or % inhib 6 1a 1 0.011 6 1a2 0.010 6 1a 3 38% @ 1 uM, 79% @ 10 uM 6 1a 4 0.016 6 1a 5 0.10 6 1a 636% @ 10 uM 6 1a 7 0.0096 6 1a 39 0.016 6 1a 40 0.21 6 1a 41 24% @ 1 uM,74% @ 10 uM 6 1a 50 42% @ 1 uM, 89% @ 10 uM 6 1a 51 31% @ 1 uM, 76% @ 10uM 6 1a 52 39% @ 1 uM, 81% @ 10 uM 6 1a 53 0.049 6 1a 54 0.0028 6 1a 550.10 6 1a 56 0.0036 16 3 1 0.081 16 3 2 38% @ 0.1 uM, 90% @ 1.0 uM 16 34 0.0024 16 3 6 0.0018 16 3 8 0.003 16 3 10 0.0025 16 3 12 0.0016 16 4102 0.0015 16 5 1 0.0014 16 5 14 0.0022 16 5 22 0.0018 16 5 33 0.0044 165 34 0.0020 16 7 31 0.0028 16 7 32 0.0015 16 11 1 0.13 16 11 9 41% @ 0.1uM, 86% @ 1 uM 16 12 10 0.0033 16 14 3 0.0049 16 14 10 0.0032

[0440] TABLE 20 Table Entry IC₅₀ (uM) or % inhibtion 1A 3 0.02 1A 1 0.045A 3 0.02 5A 4 0.01 5A 5 0.026 5A 6 0.023 5A 7 0.007 5A 9 0.067 5A 110.018 5A 12 0.006 5A 13 0.0098 5A 14 0.049 5A 16 0.008 5A 17 59% @ 10 μM5A 18 0.13 5A 19 0.092 5A 20 85% @ 1 μM 5A 22 63% @ 1 μM 5A 24 0.047 5A25 0.014 5A 26 0.005 5A 28 0.015 5A 29 0.19 5A 30 0.03 5A 31 0.02

EXAMPLE 18

[0441] The effectiveness of the compounds listed in Table 15 weredetermined in the above-described enzyme assay and in a CEM cell assay.

[0442] The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based calorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Assays wereperformed in 96-well tissue culture plates. CEM cells, a CD4⁺ cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μg/ml). An 80 μlvolume of medium containing 1×10⁴ cells was dispensed into each well ofthe tissue culture plate. To each well was added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells were incubated at 37° C. for 1 hour. A frozen culture of HIV-1was diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀=the dose of virus that infects 50% of cells in tissue culture),and a 20 μL volume of the virus sample (containing 1000 TCID₅₀ of virus)was added to wells containing test compound and to wells containing onlymedium (infected control cells). Several wells received culture mediumwithout virus (uninfected control cells). Likewise, the intrinsictoxicity of the test compound was determined by adding medium withoutvirus to several wells containing test compound. In summary, the tissueculture plates contained the following experiments: Cells DrugVirus 1. + − − 2. + + − 3. + − + 4. + + +

[0443] In experiments 2 and 4 the final concentrations of test compoundswere 1, 10, 100 and 500 μg/ml. Either azidothymidine (AZT) ordideoxyinosine (ddI) was included as a positive drug control. Testcompounds were dissolved in DMSO and diluted into tissue culture mediumso that the final DMSO concentration did not exceed 1.5% in any case.DMSO was added to all control wells at an appropriate concentration.

[0444] Following the addition of virus, cells were incubated at 37° C.in a humidified, 5% CO₂ atmosphere for 7 days. Test compounds could beadded on days 0, 2 and 5 if desired. On day 7, post-infection, the cellsin each well were resuspended and a 100 μl sample of each cellsuspension was removed for assay. A 20 μL volume of a 5 mg/ml solutionof 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)was added to each 100 μL cell suspension, and the cells were incubatedfor 4 hours at 27° C. in a 5% CO₂ environment. During this incubation,MTT is metabolically reduced by living cells resulting in the productionin the cell of a colored formazan product. To each sample was added 100μl of 10% sodium dodecylsulfate in 0.01 N HCl to lyse the cells, andsamples were incubated overnight. The absorbance at 590 nm wasdetermined for each sample using a Molecular Devices microplate reader.Absorbance values for each set of wells is compared to assess viralcontrol infection, uninfected control cell response as well as testcompound by cytotoxicity and antiviral efficacy. TABLE 21 IC₅₀ EC₅₀ TD₅₀Entry Compound (nM) (nM) (nM) 1

16 55 27 2

1 5 203 3

1 11 780 4

27 64 28 5

19 88 11 6

>100 380 425 7

3 25 39 8

85 1200 24 9

53 398 15 10

45 700 12 11

3 11 54 12

2 12 7.5 13

3 <16 14

4 15 55,000 15

5 38 16

9 80 62,000 17

4 5 59,000 18

4 19

8 20

4 21

73 22

15 18 31,000 23

2 24

3 25

60 120 167,000 26

27

5 177 300,000 28

14 76 213,000 29

5 105 196,000 30

6 154 154,000 31

10 32

5 98 17,000 33

18 68 34

67 188 35

36

310 898 37

7 <20 38

4 1,100 39

16 269 40

3 41

3 11 42

2 43

4 44

4 8 45

2 5 46

2 47

3 48

17 210 49

6 <20 50

14 51

9 52

>100 53

21 54

10 55

37

[0445] The compounds of the present invention are effective antiviralcompounds and, in particular, are effective retroviral inhibitors asshown above. Thus, the subject compounds are effective HIV proteaseinhibitors. It is contemplated that the subject compounds will alsoinhibit other retroviruses such as other lentiviruses in particularother strains of HIV, e.g. HIV-2, human T-cell leukemia virus,respiratory syncitial virus, simia immunodeficiency virus, felineleukemia virus, feline immuno-deficiency virus, hepadnavirus,cytomegalovirus and picornavirus. Thus, the subject compounds areeffective in the treatment and/or proplylaxis of retroviral infections.

[0446] The subject compounds are also effective in preventing the growthof retroviruses in a solution. Both human and animal cell cultures, suchas T-lymphocyte cultures, are utilized for a variety of well knownpurposes, such as research and diagnostic procedures includingcalibrators and controls. Prior to and during the growth and storage ofa cell culture, the subject compounds may be added to the cell culturemedium at an effective concentration to prevent the unexpected orundesired replication of a retrovirus that may inadvertently orunknowingly be present in the cell culture. The virus may be presentoriginally in the cell culture, for example HIV is known to be presentin human T-lymphocytes long before it is detectable in blood, or throughexposure to the virus. This use of the subject compounds prevents theunknowing or inadvertent exposure of a potentially lethal retrovirus toa researcher or clinician.

[0447] Compounds of the present invention can possess one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

[0448] The compounds of the present invention can be used in the form ofsalts derived from inorganic or organic acids. These salts include butare not limited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

[0449] Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

[0450] Total daily dose administered to a host in single or divideddoses may be in amounts, for example, from 0.001 to 10 mg/kg body weightdaily and more usually 0.01 to 1 mg. Dosage unit compositions maycontain such amounts of submultiples thereof to make up the daily dose.

[0451] The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration.

[0452] The dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention is selected inaccordance with a variety of factors, including the type, age, weight,sex, diet and medical condition of the patient, the severity of thedisease, the route of administration, pharmacological considerationssuch as the activity, efficacy, pharmacokinetic and toxicology profilesof the particular compound employed, whether a drug delivery system isutilized and whether the compound is administered as part of a drugcombination. Thus, the dosage regimen actually employed may vary widelyand therefore may deviate from the preferred dosage regimen set forthabove.

[0453] The compounds of the present invention may be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

[0454] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

[0455] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter and polyethylene glycols which are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[0456] Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

[0457] Liquid dosage forms for oral administration may includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions may also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[0458] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more immunomodulators, antiviral agents or otherantiinfective agents. For example, the compounds of the invention can beadministered in combination with AZT, DDI, DDC or with glucosidaseinhibitors, such as N-butyl-1-deoxynojirimycin or prodrugs thereof, forthe prophylaxis and/or treatment of AIDS. When administered as acombination, the therapeutic agents can be formulated as separatecompositions which are given at the same time or different times, or thetherapeutic agents can be given as a single composition.

[0459] The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

[0460] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound represented by the formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof, whereinR² is an alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical,which radical is optionally substituted with a radical selected from thegroup consisting of alkyl, halo, nitro, cyano, CF₃, —OR⁹, and —SR⁹,wherein R⁹ is a radical selected from the group consisting of hydrogenand alkyl; R³ is a hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl or mono-or disubstituted aminoalkyl radicals, wherein said substituents areselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; or where said aminoalkyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached, form a heterocycloalkyl or a heteroaryl radical; R⁴is an alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaralkyl,aminoalkyl or mono- or disubstituted aminoalkyl radical, wherein saidsubstituents are selected from the group consisting of alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl and heterocycloalkylalkyl radicals; or where saidaminoalkyl radical is disubstituted, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical; R⁶ is a hydrogen or alkyl radical; x is 1 or 2; t is0 or 1; and Y is O or S; and A is an alkoxy, alkenoxy, aralkoxy, alkyl,cycloalkyl, cycloalkylalkoxy, cycloalkylalkyl, aralkyl, aryl, aryloxy,heterocycloalkyl, heterocycloalkoxy, heterocycloalkylalkyl,heterocycloalkylalkoxy, heteroaralkyl, heteroaralkoxy, heteroaryloxy,heteroaryl, alkenyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl,amino, or mono- or disubstituted amino radical, wherein the substituentsare selected from the group consisting of alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyland heterocycloalkyalkyl radicals; or where said amino radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical; or isrepresented by the formula

wherein R is a hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl,cycloalkylalkanoyl, carboxyalkanoyl, alkanoyl, aralkanoyl, aroyl,aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, or mono- or disubstitutedaminocarbonyl or mono- or disubstituted aminoalkanoyl radical, whereinthe substituents are selected from the group consisting of alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl and heterocycloalkyalkyl radicals; or wherein saidaminocarbonyl or aminoalkanoyl radicals are disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical; R′ is a radical asdefined for R³ or R″SO₂—, wherein R″ is a radical as defined for R³; orR and R′ together with the nitrogen to which they are attached form aheterocycloalkyl or heteroaryl radical; R¹ is a hydrogen, —CO₂CH₃,—CH₂CO₂CH₃, —CO₂H, —CH₂CO₂H, —CH₂CH₂CONH₂, —CH₂CONH₂, —CONH₂,—CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONHCH₃, —CONH(CH₃)₂, —CH₂SO₂NH₂,—CH₂CH₂SO₂NH₂, —CH₂S[O]CH₃, —CH₂S[O]₂CH₃, —C(CH₃)₂(SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, hydroxyalkyl, cyanoalkyl,haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,alkylthioalkyl, aralkyl, heteroaralkyl, aminoalkyl or mono- ordisubstituted aminoalkyl radical, wherein said substituents are selectedfrom the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; or where said aminoalkyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached, form a heterocycloalkyl or a heteroaryl radical; andeach of R¹′ and R¹″ are independently a radical as defined for R¹; orone of R¹¹ and R¹″ together with R¹ and the carbon atoms to which R¹,R¹′ and R¹″ are attached, form a cycloalkyl radical.
 2. The compound ofclaim 1 or a pharmaceutically acceptable salt, prodrug or ester thereof,wherein R² is an alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkylradical, which radical is optionally substituted with a radical selectedfrom the group consisting of alkyl, halo and —OR⁹, wherein R⁹ is aradical selected from the group consisting of hydrogen and alkyl; R³ isa hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl or mono- or disubstitutedaminoalkyl radicals, wherein said substituents are selected from thegroup consisting of alkyl, aralkyl, cycloalkyl and cycloalkylalkylradicals; or where said aminoalkyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; R⁴ is an alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, aralkenyl or heteroaralkyl radical; R⁶ is a hydrogen oralkyl radical; x is 1 or 2; t is 0 or 1; and Y is O or S; and A is analkoxy, alkenoxy, aralkoxy, alkyl, cycloalkyl, cycloalkylalkoxy,cycloalkylalkyl, aralkyl, aryl, aryloxy, heterocycloalkyl,heterocycloalkoxy, heterocycloalkylalkyl, heterocycloalkylalkoxy,heteroaralkyl, heteroaralkoxy, heteroaryloxy, heteroaryl, hydroxyalkyl,amino, or mono- or disubstituted amino radical, wherein the substituentsare selected from the group consisting of alkyl, aralkyl, heteroaryl,heteroaralkyl, heterocycloalkyl and heterocycloalkyalkyl radicals; orwhere said amino radical is disubstituted, said substituents along withthe nitrogen atom to which they are attached form a heterocycloalkylradical; or is represented by the formula

wherein R is a hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, carboxyalkanoyl, alkanoyl, aralkanoyl, aroyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, cycloalkyl, aralkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, or mono- or disubstitutedaminocarbonyl or mono- or disubstituted aminoalkanoyl radical, whereinthe substituents are selected from the group consisting of alkyl,aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkyalkyl radicals; or wherein said aminocarbonyl oraminoalkanoyl radicals are disubstituted, said substituents along withthe nitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical; R′ is a hydrogen, alkyl or aralkyl radical orR″SO₂—, wherein R″ is a radical as defined for R³; or R and R′ togetherwith the nitrogen to which they are attached form a heterocycloalkyl orheteroaryl radical; R¹ is a hydrogen, —CO₂CH₃, —CH₂CO₂CH₃, —CO₂H,—CH₂CO₂H, —CH₂CH₂CONH₂, —CH₂CONH₂, —CONH₂, —CH₂C(O)NHCH₃,—CH₂C(O)N(CH₃)₂, —CONHCH₃, —CONH(CH₃)₂, —CH₂SO₂NH₂, —CH₂CH₂SO₂NH₂,—CH₂S[O]CH₃, —CH₂S[O]₂CH₃, —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, hydroxyalkyl, cyanoalkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, alkylthioalkyl, aralkyl,heteroaralkyl, aminoalkyl or mono- or disubstituted aminoalkyl radical,wherein said substituents are selected from the group consisting ofalkyl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; or where said aminoalkyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached, form a heterocycloalkyl or a heteroaryl radical; andeach of R¹′ and R¹″ are independently a radical as defined for R¹; orone of R¹′ and R¹″ together with R¹ and the carbon atoms to which R¹,R¹′ and R¹″ are attached, form a cycloalkyl radical.
 3. The compound ofclaim 2 or a pharmaceutically acceptable salt, prodrug or ester thereof,wherein R² is an alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkylradical, which radical is optionally substituted with a radical selectedfrom the group consisting of alkyl, halo and —OR⁹, wherein R⁹ is aradical selected from the group consisting of hydrogen and alkyl; R³ isa hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl or mono- or dialkyl substitutedaminoalkyl radical; R⁴ is an alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,aralkenyl or heteroaralkyl radical; R⁶ is a hydrogen or alkyl radical; xis 1 or 2; t is 0 or 1; and Y is O or S; and A is an alkoxy, alkenoxy,aralkoxy, alkyl, cycloalkyl, aryl, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylalkyl, heteroaralkoxy, heteroaryl, amino, or mono- ordisubstituted amino radical, wherein the substituents are selected fromthe group consisting of alkyl and aralkyl radicals; or is represented bythe formula

wherein R is a hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, carboxyalkanoyl, alkanoyl, aroyl, heteroaroyl, alkyl,aralkyl, aminocarbonyl, aminoalkanoyl, or mono- or disubstitutedaminocarbonyl or mono- or disubstituted aminoalkanoyl radical, whereinthe substituents are selected from the group consisting of alkyl andaralkyl radicals; R′ is a hydrogen, alkyl or aralkyl radical or R″SO₂—,wherein R″ is a radical as defined for R³; or R and R′ together with thenitrogen to which they are attached form a heterocycloalkyl orheteroaryl radical; R¹ is a hydrogen, —CO₂CH₃, —CH₂CO₂CH₃, —CO₂H,—CH₂CO₂H, —CH₂CH₂CONH₂, —CH₂CONH₂, —CONH₂, —CH₂C(O)NHCH₃,—CH₂C(O)N(CH₃)₂, —CONHCH₃, —CONH(CH₃)₂, —CH₂SO₂NH₂, —CH₂CH₂SO₂NH₂,—CH₂S[O]CH₃, —CH₂S[O]₂CH₃, —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, hydroxyalkyl, cyanoalkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, alkylthioalkyl, aralkyl,heteroaralkyl, aminoalkyl or mono- or disubstituted aminoalkyl radical,wherein said substituents are selected from the group consisting ofalkyl and aralkyl radicals; and R¹′ is a hydrogen, alkyl or aralkyl; andR¹″ is a hydrogen, alkyl, —CO₂CH₃ or —CONH₂; or one of R¹′ and R¹″together with R¹ and the carbon atoms to which R¹, R¹′ and R¹″ areattached, form a cycloalkyl radical.
 4. The compound of claim 3 or apharmaceutically acceptable salt, prodrug or ester thereof, wherein R²is an alkyl, cycloalkylalkyl or aralkyl radical, which radical isoptionally substituted with a radical selected from the group consistingof alkyl, halo and —OR⁹, wherein R⁹ is a radical selected from the groupconsisting of hydrogen and alkyl; R³ is a hydrogen, alkyl, alkenyl,alkynyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl or mono- or dialkyl substituted aminoalkylradical; R⁴ is an alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, aralkenyl or heteroaralkylradical; R⁶ is a hydrogen or alkyl radical; x is 1 or 2; t is 0 or 1;and Y is O or S; and A is an alkoxy, alkenoxy, aralkoxy, alkyl,cycloalkyl, aryl, heterocycloalkyl, heterocycloalkoxy,heterocycloalkylalkyl, heteroaralkoxy, heteroaryl, amino, or mono- ordisubstituted amino radical, wherein the substituents are selected fromthe group consisting of alkyl and aralkyl radicals; or is represented bythe formula

wherein R is a hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, carboxyalkanoyl, alkanoyl, aroyl, heteroaroyl, alkyl,aralkyl, aminocarbonyl, aminoalkanoyl, or mono- or disubstitutedaminocarbonyl or mono- or disubstituted aminoalkanoyl radical, whereinthe substituents are selected from the group consisting of alkyl andaralkyl radicals; R′ is a hydrogen, alkyl or aralkyl radical or R″SO₂—,wherein R″ is a radical as defined for R³; or R and R′ together with thenitrogen to which they are attached form a heterocycloalkyl orheteroaryl radical; R¹ is a hydrogen, —CO₂H, —CH₂CO₂H, —CH₂CH₂CONH₂,—CH₂CONH₂, —CONH₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONHCH₃, —CONH(CH₃)2, —CH₂SO₂NH₂, —CH₂CH₂SO₂NH₂, alkyl, hydroxyalkyl, cyanoalkyl, alkynyl,cycloalkylalkyl, alkylthioalkyl, aralkyl or heteroaralkyl radical; andR¹′ is a hydrogen, alkyl or aralkyl; and R¹″ is a hydrogen, alkyl,—CO₂CH₃ or —CONH₂; or one of R¹′ and R¹″ together with R¹ and the carbonatoms to which R¹, R¹′ and R¹″ are attached, form a cycloalkyl radical;with the proviso that alkyl, alone or in combination, is astraight-chain or branched-chain hydrocarbon radical containing from oneto eight carbon atoms; alkenyl, alone or in combination, is astraight-chain or branched-chain hydrocarbon radical having at least onedouble bond and containing from two to eight carbon atoms; alkynyl,alone or in combination, is a straight-chain or branched-chainhydrocarbon radical having at least one triple bond and containing fromtwo to ten carbon atoms; and cycloalkyl, alone or in combination, is ahydrocarbon ring containing from three to eight carbon atoms.
 5. Thecompound of claim 4 or a pharmaceutically acceptable salt, prodrug orester thereof, wherein R² is an alkyl, cycloalkylalkyl or aralkylradical, which radical is optionally substituted with a radical selectedfrom the group consisting of alkyl, halo and —OR⁹, wherein R⁹ is aradical selected from the group consisting of hydrogen and alkyl; R³ isa hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl or mono-or dialkyl substituted aminoalkyl radical; R⁴ is an alkyl, haloalkyl,alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, aralkenyl or heteroaralkyl radical; R⁶ is a hydrogen oralkyl radical; x is 1 or 2; t is 0 or 1; and Y is O or S; and A is analkoxy, alkenoxy, aralkoxy, alkyl, cycloalkyl, aryl, heterocycloalkyl,heterocycloalkoxy, heterocycloalkylalkyl, heteroaralkoxy, heteroaryl,amino, or mono- or disubstituted amino radical, wherein the substituentsare selected from the group consisting of alkyl and aralkyl radicals; oris represented by the formula

wherein R is a hydrogen, alkoxycarbonyl, aralkoxycarbonyl,alkylcarbonyl, carboxyalkanoyl, alkanoyl, aroyl, heteroaroyl, alkyl,aralkyl, aminocarbonyl, aminoalkanoyl, or mono- or disubstitutedaminocarbonyl or mono- or disubstituted aminoalkanoyl radical, whereinthe substituents are selected from the group consisting of alkyl andaralkyl radicals; R′ is a hydrogen, alkyl or aralkyl radical or R″SO₂—,wherein R¹ is a radical as defined for R³; or R and R′ together with thenitrogen to which they are attached form a heterocycloalkyl orheteroaryl radical; R¹ is a hydrogen, —CO₂H, —CH₂CO₂H, —CH₂CH₂CONH₂,—CH₂CONH₂, —CONH₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONHCH₃,—CONH(CH₃)₂, —CH₂SO₂NH₂, —CH₂CH₂SO₂NH₂, alkyl, hydroxyalkyl, cyanoalkyl,alkynyl, cycloalkylalkyl, alkylthioalkyl, aralkyl or heteroaralkylradical; and R¹′ is a hydrogen, alkyl or aralkyl; and R¹″ is a hydrogen,alkyl, —CO₂CH₃ or —CONH₂; or one of R¹′ and R¹″ together with R¹ and thecarbon atoms to which R¹, R¹′ and R¹″ are attached, form a cycloalkylradical; with the proviso that alkyl, alone or in combination, is astraight-chain or branched-chain hydrocarbon radical containing from oneto five carbon atoms; alkenyl, alone or in combination, is astraight-chain or branched-chain hydrocarbon radical having at least onedouble bond and containing from two to five carbon atoms; alkynyl, aloneor in combination, is a straight-chain or branched-chain hydrocarbonradical having at least one triple bond and containing from two to fivecarbon atoms; and cycloalkyl, alone or in combination, is a hydrocarbonring containing from three to eight carbon atoms; and with the provisothat when R² is cycloalkylalkyl and t is 0, R′ is a group other thanalkoxycarbonyl.
 6. The compound of claim 5 or a pharmaceuticallyacceptable salt, prodrug or ester thereof, wherein R² is butyl,cyclohexylmethyl, benzyl, 4-fluorobenzyl or naphthylmethyl; R³ ismethyl, ethyl, propyl, butyl, pentyl, hexyl, iso-butyl, iso-amyl,3-methoxypropyl, 3-methylthiopropyl, 4-methylthiobutyl,4-methylsulfonylbutyl, 2-dimethylaminoethyl, 2-(1-morpholino)ethyl,4-hydroxybutyl, allyl, propargyl, cyclohexylmethyl, cyclopropylmethyl,phenyl, benzyl, 4-fluorobenzyl, 4-methoxybenzyl, 1-phenylethyl,2-phenylethyl, naphthylmethyl, 3-pyridylmethyl or 4-pyridylmethyl; R⁴ ismethyl, ethyl, propyl, butyl, ethenyl, chloromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, chlorophenyl,fluorophenyl, hydroxyphenyl, methylphenyl, methoxyphenyl, ethoxyphenyl,methylthiophenyl, methylsulfoxyphenyl, methylsulfonylphenyl,acetamidophenyl., methoxycarbonylphenyl, dimethylaminophenyl,nitrophenyl, trifluoromethylphenyl, benzyl, 2-phenylethenyl or thienyl;R⁶ is hydrogen; x is 2; t is 0 or 1; and Y is 0; and A is methyl,cyclohexyl, cyclopentyl, cycloheptyl, 1,2,3,4-tetrahydronaphthyl,naphthyl, quinolinyl, indolyl, pyridyl, methylpyridyl, furanyl,thiophenyl, oxazolyl, thiazolyl, phenyl, methylphenyl, ethylphenyl,dimethylphenyl, iso-propylphenyl, chlorophenyl, hydroxyphenyl,methoxyphenyl, methylsulfonylphenyl, methylsulfonylmethylphenyl,carboxyphenyl, aminocarbonylphenyl, methylhydroxyphenyl,methylnitrophenyl, methylaminophenyl, methyl-N,N-dimethylaminophenyl,t-butoxy, benzyloxy, pyridylmethoxy, 3-propenoxy, hydroxypyridylmethoxy,aminopyridylmethoxy, pyrimidinylmethoxy, N-oxo-pyrimidinylmethoxy,thiazolylmethoxy, tetrahydrothiophenoxy, 1,1-dioxotetrahydrothiophenoxy,tetrahydrofuranoxy, methylamino, benzylamino or isopropylamino; or isrepresented by the formula

wherein R is hydrogen, acetyl, phenoxyacetyl, methoxyacetyl,naphthaloxyacetyl, succinoyl, 2-methylpropionoyl, 2-hydroxypropionoyl,t-butoxycarbonyl, benzyloxycarbonyl, methoxybenzyloxycarbonyl,aminocarbonyl, quinolinylcarbonyl, N-methylglycinyl orN,N-dimethylglycinyl; R′ is hydrogen, benzyl or methyl; or R and R′together with the nitrogen to which they are attached form pyrrolyl; R¹is hydrogen, —CO₂H, —CH₂CO₂H, —CH₂CH₂CONH₂, —CH₂CONH₂, —CONH₂,—CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CONHCH₃, —CONH(CH₃)₂, —CH₂SO₂NH₂,—CH₂CH₂SO₂NH₂, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, 3-methylbutyl, cyclohexylmethyl, benzyl,hydroxybenzyl, imidazoyl, imidazoylmethyl, cyanomethyl,methylthiomethyl, propargyl or hydroxyethyl; and R¹′ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, phenylethyl,phenylpropyl, phenylbutyl or 4,4-diphenylbutyl; and R¹″ is hydrogen,methyl, —CO₂CH₃ or —CONH₂; or one of R¹′ and R¹″ together with R¹ andthe carbon atoms to which R¹, R¹′ and R¹″ are attached, form cyclobutyl,cyclopentyl or cyclohexyl; with the proviso that when R² iscyclohexylmethyl and t is 0, R′ is a group other than t-butoxycarbonyl.7. The compound of claim 1 which is:Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;N1-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide;N1-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethyloxycarbonyl)amino]butanediamide;N1-[2R-hydroxy-3[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide;N1-[2R-hydroxy-3[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(phenylmethyloxycarbonyl)amino]butanediamide;2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide;2S-[[(methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide;N1-[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-N-4-methyl-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide;[3-[[2-hydroxy-3-[N-(3-methylbutyl)-N-(phenylsufonyl)amino]-1-(phenylmethyl)propyl]amino]-2-methyl-3-oxopropyl]-,(4-methoxyphenyl)methyl ester, [1S-[1R*(S*),2S*]]-; Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-methoxyyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrothiophen-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-S-tetrahydrofuran-3-yl-ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methyl ester; Benzamide,N-[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl;Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidylmethyl ester; or Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl.
 8. A compound represented bythe formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof, whereineach of p¹ and p² independently represent hydrogen, alkoxycarbonyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, or mono- or disubstituted aminocarbonyl or mono- ordisubstituted aminoalkanoyl radical, wherein the substituents areselected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkyalkyl radicals; or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical; R² isan alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical, whichradicals are optionally substituted with a group selected from alkyl andhalogen radicals, nitro, cyano, CF₃, —OR⁹, —SR⁹, wherein R⁹ is ahydrogen or alkyl radical; R³ is a hydrogen, alkyl, haloalkyl, alkenyl,alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl or mono- or disubstituted aminoalkyl radical,wherein said substituents are selected from the group consisting ofalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroaralkyl, heterocycloalkyl and heterocycloalkylalkyl radicals; orwhere the aminoalkyl radical is disubstituted, said substituents alongwith the nitrogen atom to which they are attached, form aheterocycloalkyl or a heteroaryl radical; and R⁴ is a radical as definedby R³ except for hydrogen.
 9. The compound of claim 8, wherein each ofP¹ and P² independently represent a hydrogen, alkoxycarbonyl,aralkyloxycarbonyl, heteroaralkoxycarbonyl, aroyl, heteroaroyl, alkanoylor cycloalkanoyl radical; R² is a cycloalkylalkyl, aralkyl or alkylradical; R³ is an alkyl, cycloalkyl or cycloalkylalkyl radical; and R⁴is an aryl, alkyl, heteroaryl or aryl radical.
 10. The compound of claim9, wherein P¹ and P² independently represent 3-pyridylmethyloxycarbonyl,3-pyridylmethyloxycarbonyl N-oxide, 4-pyridylmethyloxycarbonyl,4-pyridylmethyloxycarbonyl N-oxide, 5-pyrimidylmethyloxycarbonyl,tert-butyloxycarbonyl, allyloxycarbonyl, 2-propyloxycarbonyl,benzyloxycarbonyl, cycloheptylcarbonyl, cyclohexylcarbonyl,cyclopentylcarbonyl, benzoyl, 4-pyridylcarbonyl, 2-methylbenzoyl,3-methylbenzoyl, 4-methylbenzoyl, 2-chlorobenzoyl, 2-ethylbenzoyl,2,6-dimethylbenzoyl, 2,3-dimethylbenzoyl, 2,4-dimethylbenzoyl or2,5-dimethylbenzoyl; R² is benzyl, cyclohexylmethyl, 2-naphthylmethyl,para-fluorobenzyl, para-methoxybenzyl, isobutyl or n-butyl; R³ isisobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl or n-propyl;and R⁴ is phenyl, para-methoxyphenyl, para-cyanophenyl,para-chlorophenyl, para-hydroxyphenyl, para-nitrophenyl,para-fluorophenyl, 2-naphthyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridylor 4-pyridyl N-oxide; with the proviso that when R² is cyclohexylmethyl,each of P¹ and P² independently represent a group other thantert-butyloxycarbonyl.
 11. A compound of claim 8 which is:Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-fluorophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-nitrophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-chlorophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-acetamidophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-aminophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(4-fluorophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(4-nitrophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(4-chlorophenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(4-fluorophenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(2-methylpropyl)(4-fluorophenylsulfonyl)amino]-1S-(4-fluorophenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(cyclohexylmethyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(cyclohexyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Phenylmethyl[2R-hydroxy-3-[(propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate;Pentanamide,2S-[[(dimethylamino)acetyl]amino]-N-2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl;Pentanamide,2S-[[(methylamino)acetyl]amino]-N-2R-hydroxy-3-[(4-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl;Pentanamide,2S-[[(dimethylamino)acetyl]amino]-N-2R-hydroxy-3-[(4-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl;[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine;2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine;[2R-hydroxy-3-[(phenylsulfonyl)(3-methylbutyl)amino]-1S-(phenylmethyl)propylamine;[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propylamine;[2R-hydroxy-3-[(phenylsulfonyl)(cyclohexylmethyl)amino]-1S-(phenylmethyl)propylamine;[2R-hydroxy-3-[(phenylsulfonyl)(cyclohexyl)amino]-1S-(phenylmethyl)propylamine;4-Pyridinecarboxamide, N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]; Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2,6-dimethyl;Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl;Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-ethyl;Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-chloro;Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, N-oxide; Carbamic acid,[2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,4-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,4-pyridylmethyl ester, N-oxide; Carbamic acid,[2R-hydroxy-3-[[(4-chlorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester; or Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidylmethyl ester.
 12. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier.
 13. Apharmaceutical composition comprising a compound of claim 8 and apharmaceutically acceptable carrier.
 14. Method of inhibiting aretroviral protease comprising administering an effective amount of acompound of claim
 1. 15. Method of inhibiting a retroviral proteasecomprising administering an effective amount of a compound of claim 8.16. Method of treating a retroviral infection comprising administeringan effective amount of a composition of claim
 12. 17. Method of treatinga retroviral infection comprising administering an effective amount of acomposition of claim
 13. 18. Method of preventing replication of aretrovirus suspected of being present in a solution comprisingadministering an effective amount of a compound of claim
 1. 19. Methodof preventing replication of a retrovirus suspected of being present ina solution comprising administering an effective amount of a compound ofclaim 8.